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(Chest. 2006;130:1334-1345.)
© 2006 American College of Chest Physicians

Feasibility of Retinoids for the Treatment of Emphysema Study*

Michael D. Roth, MD, FCCP; John E. Connett, PhD; Jeanine M. D’Armiento, MD, PhD; Robert F. Foronjy, MD; Paul J. Friedman, MD; Jonathan G. Goldin, MbChb, PhD; Thomas A. Louis, PhD; Jenny T. Mao, MD, FCCP; Josephia R. Muindi, MD, PhD; George T. O’Connor, MD, FCCP; Joe W. Ramsdell, MD, FCCP; Andrew L. Ries, MD, FCCP; Steven M. Scharf, MD, PhD; Neil W. Schluger, MD; Frank C. Sciurba, MD, FCCP; Melissa A. Skeans, MS; Robert E. Walter, MD; Christine H. Wendt, MD; Robert A. Wise, MD; for the FORTE Study Investigators{dagger}

* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Roth and Mao) and Radiology (Dr. Goldin), University of California, Los Angeles, CA; Boston University (Drs. O’Connor and Walter), Boston, MA; Columbia University (Drs. D’Armiento, Foronjy, and Schluger), New York, NY; Johns Hopkins University (Drs. Louis and Wise), Baltimore, MD; Roswell Park Cancer Institute (Dr. Muindi), Buffalo, NY; University of California, San Diego (Drs. Friedman, Ramsdell, and Ries), San Diego, CA; University of Maryland (Dr. Scharf), Baltimore, MD; University of Pittsburgh (Dr. Sciurba), Pittsburgh, PA; and the Divisions of Pulmonary and Critical Care Medicine (Dr. Wendt) and Biostatistics/CCBR (Ms. Skeans and Dr. Connett), University of Minnesota, Twin Cities, MN. {dagger} For a list of FORTE investigators see Appendix.

Correspondence to: Michael D. Roth, MD, FCCP; Division of Pulmonary and Critical Care; Department of Medicine, CHS 37–131; David Geffen School of Medicine at UCLA; Los Angeles, CA 90095-1690; e-mail: mroth{at}mednet.ucle.edu

Abstract

Background: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema.

Methods: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (DLCO) [37.1 ± 12.0% of predicted] and CT density mask (38.5 ± 12.8% of voxels <– 910 Hounsfield units) [mean ± SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period.

Results: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in DLCO (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild.

Conclusions: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in DLCO, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Key Words: clinical trial • CT scan • emphysema • health-related quality of life • pulmonary function test • radiograph • retinoic acid

Emphysema results from a loss of alveolar septa and enlargement of terminal airspaces, events that lead to a reduction in elastic recoil, hyperinflation, airflow obstruction, and a loss of alveolar-capillary surface area available for gas diffusion. While these pathophysiologic consequences are generally considered progressive and irreversible, this view was recently challenged by animal models in which both elastase-induced and smoking-related emphysema improved following treatment with retinoids.1234

Retinoids are normally derived from dietary carotenoids and retinol, and they regulate gene expression by interacting with specific nuclear receptors.56 High concentrations of retinoic acid accumulate within the lung during organ development and are temporally associated with the process of alveolar septation.7 The essential role that retinoids play in the generation of alveoli has recently been confirmed by studies89 involving retinoid receptor knock-out animals. In addition, in vitro human studies10 have demonstrated that retinoic acid can regulate an array of cellular and molecular pathways involved in lung remodeling.

This background provides the rationale for studying retinoids as a potential treatment for human emphysema. However, not all emphysema models have demonstrated positive effects of retinoids on lung repair.111213 It is also difficult to draw comparisons between short-term animal models of alveolar destruction and the complex pathophysiology of human disease. The Feasibility of Retinoids for the Treatment of Emphysema (FORTE) study was established by the National Institutes of Health/National Heart, Lung, and Blood Institute as an initial step in evaluating the clinical feasibility of retinoid-based therapy. The primary clinical outcomes from the FORTE study are described in this report and address the following key questions: (1) can retinoids be administered safely to emphysema patients for an extended period of time; (2) how will administration of 13-cis retinoic acid (13-cRA) compare to administration of all-trans retinoic acid (ATRA); (3) are there dose- and/or time-dependent relationships between exposures and outcomes; and (4) can specific physiologic, symptomatic, or radiologic measures of emphysema be identified as candidates for monitoring responses in future studies?

Methods and Materials

Study Design
Emphysema patients were enrolled at five university hospitals according to a randomized, double-blind, placebo-controlled design. The protocol was approved by each institutional review board, and written informed consent obtained from all participants. Subjects were initially randomized into one of three treatment arms (low-dose [LD]-ATRA, 1 mg/kg; high-dose [HD]-ATRA, 2 mg/kg; or 13-cRA, 1 mg/kg) and then further randomized in phase 1 to begin a 6-month treatment with either active drug or placebo (Fig 1 ). 13-cRA was taken daily, while ATRA was administered for only 4 days each week to reduce the induction of metabolizing enzymes.1415 In phase 2, participants were crossed over within each arm for 3 additional months. Subjects continued on standard medical therapy and returned for a final assessment at 18 months.


Figure 1
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  		Figure 1.. Study protocol and participation. One hundred forty-eight subjects were initially randomized into one of three treatment arms (LD-ATRA, HD-ATRA, and 13-cRA) and then further randomized at the start of phase 1 to begin treatment with either active drug or placebo. The placebo group was thereby subdivided between the three treatment arms in order to control for the different drug doses and administration schedules. Active drugs and placebo were administered as matched 10-mg gel capsules with the number of capsules adjusted according to patient’s weight. LD-ATRA (1 mg/kg), HD-ATRA (2 mg/kg), or matching doses of placebo were administered for 4 consecutive days each week, while 13-cRA (1 mg/kg) and its matching placebo were administered daily. After a 6-month placebo-controlled period (phase 1), subjects receiving active treatment were crossed over to placebo and vice versa for a 3-month period (phase 2). Subjects were observed for an additional 9 months before final assessment. The numbers of participants completing each phase of the study are indicated in parentheses. pts = patients.

 
Participant Selection
Entry criteria included age > 45 years, FEV1 25 to 80% of predicted, diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 80% of predicted, visual evidence of emphysema occupying ≥ 10% of the lung on CT scan, and willingness to undergo bronchoscopy. Participants were excluded for a Karnofsky score < 70%; excessive airway hyperreactivity; resting oxygen saturation < 90% or PCO2 > 45 mm Hg; use of systemic corticosteroids within 2 months or tobacco within 6 months; hyperlipidemia; a history of clinical depression; concurrent use of medications that alter the metabolism of retinoids; or other significant illnesses including cancer, liver disease, or heart failure. Women of child-bearing potential were required to use two forms of contraception or abstinence.

Monitoring and Outcome Measures
Safety monitoring was performed 2 weeks after the start of each phase and then monthly by physical examinations, a Center for Epidemiologic Studies Depression Scale, and standard blood tests. Pulmonary function testing and quality of life (QOL) questionnaires were obtained at baseline and at 3, 6, 9, and 18 months. Chest CT scans were obtained at screening and at 6, 9, and 18 months. Plasma retinoid concentrations were determined by high-pressure liquid chromatography at baseline, 3 h following the first dose of drug, and 3 h after dosing on either the 4-week or 12-week follow-up visits.15 Participants with an FEV1 ≥ 30% of predicted also underwent bronchoscopy at baseline and again after either 2 weeks or 16 weeks of treatment unless excluded for specific medical contraindications or at investigator discretion.

Pulmonary function tests were performed by qualified personnel,16 and serial testing for each subject was performed by the same technician and on the same equipment whenever possible. Spirometry, DLCO, DLCO/alveolar volume (VA), and plethysmographic lung volumes were measured according to American Thoracic Society standards,171819 with predicted values according to Hankinson et al20 and Crapo et al,2122 and with DLCO adjusted for hemoglobin according to Cotes et al.23 QOL and functional status were assessed with the St. George Respiratory Questionnaire (SGRQ),24 University of California, San Diego Shortness of Breath Questionnaire,25 and Short Form-36 health profile.26

Radiology technologists were trained in a standard imaging protocol and certified by the Radiology Core through a combination of site visits and water phantom scans. Subjects were coached to obtain CT scans at full inspiration, and serial studies were obtained on the same scanner whenever possible. A water phantom (GE; Milwaukee, WI) was scanned at each center, and the reconstruction kernels were selected to provide equivalent images across institutions.27 Ten-millimeter collimation was used (no overlap), and images were transmitted in digital format to the Radiology Core. Scans were checked for data integrity and compliance with the imaging protocol, and then segmented using an automated technique.28 Image analysis was performed to determine lung volume and the percentage of emphysema by density mask (percentage of total lung voxels < – 910 Hounsfield units [HU]).2930 Density mask scores were not adjusted for CT-measured lung volume due to possible independent effects of treatment on these parameters.

Statistical Analysis
Primary outcome analyses were performed on subjects who completed therapy during phase 1. Pulmonary function and QOL outcomes were assessed as the change from baseline, with comparisons made between treatment groups and placebo at 6 months. The within-group change over time was also assessed comparing baseline and 6-month data to that at 18 months. Baseline differences were assessed by analysis of variance F tests for continuous variables and {chi}2 statistics for categorical variables. Nonparametric assessments were performed on outcome and adverse events data that did not conform to assumptions of normality. Differences in outcomes were evaluated using the Wilcoxon rank-sum test for two-group comparisons and the Kruskal-Wallis test for comparisons among three or more groups. Results are presented as means ± 1 SEM unless otherwise stated; p values and confidence intervals were not corrected for multiple comparisons.

Results

Subject Characteristics
One hundred forty-eight participants were randomized over 18 months, achieving 49% of the original recruitment goal. Major barriers to enrollment included advanced disease, airway hyperreactivity, hyperlipidemia, concurrent illnesses, prior cancer, and use of prohibited medications. The study groups were well balanced, representing individuals with moderate-to-severe obstructive lung disease and significant emphysema (Table 1 ). All but two participants identified themselves as non-Hispanic white. Due to problems with availability of ATRA, more participants were assigned to the 13-cRA study arm than originally designed. Of those randomized, 87% of the subjects completed phase 1 (Fig 1), and this cohort was evaluated for treatment-related effects. There were no significant differences in the baseline characteristics of this subpopulation compared to the entire randomized group. Adherence to treatment, calculated by monthly pill counts, averaged 93.2% for placebo, 91.3% for LD-ATRA, 90.2% for HD-ATRA, and 83.7% for 13-cRA.


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  		Table 1.. Baseline Characteristics at Enrollment*

 
Plasma Drug Levels
Distinct differences in the metabolism and biodistribution of ATRA were apparent between the treatment regimens (Fig 2 ). Plasma levels measured after the first dose were approximately twofold higher in those treated with HD-ATRA (190.7 ± 35 ng/mL) as compared to LD-ATRA (98.0 ± 21.8 ng/mL), while initial levels in those treated with 13-cRA were very low (16.6 ± 2.38 ng/mL). ATRA levels decreased significantly in both ATRA groups over time, but HD-ATRA maintained levels that averaged 4.6-fold higher than LD-ATRA (p < 0.01). In contrast, ATRA levels increased slightly over time in those receiving 13-cRA (p < 0.01).


Figure 2
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  		Figure 2.. Impact of drug and dose on plasma ATRA levels. Plasma ATRA levels were determined by high-pressure liquid chromatography on samples collected 3 h after the first dose of drug (baseline) and again at 3 h after dosing during either the fourth or twelfth week of therapy (follow-up). *p < 0.02 compared to baseline LD-ATRA. {dagger}p < 0.01 comparing initial to follow-up level.

 
Pulmonary Function Outcomes
There were no statistically significant changes over time in measured FEV1, FVC, or FEV1/FVC ratio (Table 2 ; Fig 3 , top, A). However, given the variability of the repeated measurements of FEV1 in the placebo group during phase 1, post hoc analysis suggested that a sample size of 224 subjects per group would have been required to detect a 10% change in this parameter (power = 0.9, {alpha} = 0.05). There was, on average, a 6% absolute decrease in percentage of predicted total lung capacity (TLC) and a 19% absolute decrease in percentage of predicted residual volume (RV) in subjects treated for 6 months with LD-ATRA. While statistically significant, this isolated change did not correlate with any other outcome measure. Of more interest was the observed decrease in DLCO at 6 months in subjects treated with HD-ATRA (Table 2; Fig 3, center, B; – 4.48 ± 1.01% of predicted; p < 0.001). The same pattern was observed to a lesser degree at 3 months, as well as in subjects treated with LD-ATRA and 13-cRA. The magnitude of the decline in DLCO at 6 months also correlated with the initial plasma ATRA levels (Spearman correlation coefficient, – 0.2559; p < 0.01). DLCO recovered significantly with time after retinoid therapy was discontinued (p < 0.05), and by the 18-month visit had returned to equal or slightly higher than baseline levels in the HD-ATRA group.


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  		Table 2.. Outcome Measures at 6 Months and 18 Months for Subjects Who Completed Phase 1*

 

Figure 3
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  		Figure 3.. Changes in outcome measures during active treatment and follow-up. Left panels: Changes from baseline at 3 months and 6 months are plotted for serial measurements of FEV1 (top, A), DLCO (center, B), and SGRQ (bottom, C) [sample size for placebo, n = 33; LD-ATRA, n = 26; HD-ATRA, n = 25; and 13-cRA, n = 45]. Right panels: Changes from baseline at 6, 9, and 18 months are plotted for the subjects initially treated with one of the study drugs. Only subjects who completed both the phase 2 and observation periods are displayed in the right panels (sample size for LD-ATRA, n = 22; HD-ATRA, n = 20; 13-cRA, n = 37), and no placebo group is included due to the crossover to drug treatment at 6 months. Results are expressed as mean ± SEM *p < 0.05 compared to placebo. {dagger}p < 0.05 compared to 6-month value.

 
Health-Related QOL Outcomes
There were no statistically-significant changes in SGRQ scores, compared to baseline, at the end of phase 1. However, there was a clinically and statistically significant decrease from baseline (an improvement) in the total score 3 months later (at 9 months) in subjects treated with HD-ATRA (– 4.44 ± 1.71 points, p = 0.015) but not in the other treatment groups (Table 2; Fig 3, bottom, C). Individual subscores also decreased on average by ≥ 4 points in the HD-ATRA group. The change in total score waned by 18 months (– 3.22 ± 2.09 points). Similar trends were observed in the Shortness of Breath Questionnaire at 9 months (– 6.52 ± 2.43 points, HD-ATRA) but did not reach statistical significance.

Changes in CT Density Mask Scores
Similar to other outcomes, average density mask scores did not change significantly by the end of phase 1 (Table 2). CT outcomes were also carefully assessed at the 9-month visit, with no overall improvements identified for the treatment groups. An exploratory responder/nonresponder analysis was then performed to assess whether a subset of subjects had improvements in their density mask score that exceeded normal scan-to-scan variability. Normal variability was defined by comparing values obtained at baseline to those obtained at 6 months for the placebo group (Fig 4 ). The breath-hold volume was found to be highly reproducible (coefficient of variation, 4.3 ± 0.77%), and an absolute decrease in density mask score of ≥ 7% was identified as the 95% confidence level for determining responders. Using this definition, only 1 of the 33 placebo-treated subjects had an emphysema score that decreased at either 6 months or 9 months (3%), while 5 of 25 subjects (20%) in the HD-ATRA group exhibited significant decreases in the percentage of voxels <– 910 HU at 9 months (Fig 5 ; p < 0.05, Fisher exact test). Collectively, only 4 of 66 participants (6%) in the other treatment groups were identified as CT responders. On closer inspection, it was noted that the subject with the greatest decrease in low-density voxels on CT had the highest baseline ATRA level (733 ng/mL), and that ATRA levels correlated with the magnitude of change in density mask score at 9 months (Fig 5; Spearman correlation coefficient, – 0.415; p = 0.055).


Figure 4
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  		Figure 4.. Reproducibility of breath-hold volumes and density mask scores over time in the placebo group. Left, A: Subjects were carefully instructed to hold their breath at maximal inspiration (TLC) while CT images were obtained in order to limit scan-to-scan variability. Reproducibility of this maneuver was assessed by comparing CT-calculated breath-hold volumes at baseline to those at 6 months for the placebo group (coefficient of variation, 4.3 ± 0.77%). Right, B: Normal scan-to-scan variation in the density mask score (change in percentage of voxels <– 910 HU) was calculated from the change over time, comparing baseline and 6-month scans for each individual in the placebo group. A distribution analysis was performed, and a 95% confidence interval was determined. Based on this distribution, a threshold for identifying potential treatment responders was established at a ≥ 7% absolute decrease in voxels <– 910 HU.

 

Figure 5
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  		Figure 5.. Serial CT scans identify a subset of subjects in which density mask scores decreased in response to treatment with HD-ATRA. Left, A: Subjects were classified into two subsets based on whether or not the change in their density mask scores at 9 months, compared to baseline, exceeded the 95% confidence interval for the placebo group (≥ 7% absolute decrease in voxels <– 910 HU). Density mask scores are shown at baseline, 6 months, and 9 months for each individual in the HD-ATRA group whose score decreased significantly by this criteria (5 of 25 subjects, 20%). Group means (± SE) are shown for the baseline and 9-month time points. By comparison, only 1 of the 33 placebo-treated subjects (3%) exhibited a significant decrease in low-density voxels on follow-up CT scans at either 6 months or 9 months (p < 0.05; Fig 4). Right, B: The absolute change in density mask score at 9 months (percentage of voxels <– 910) was plotted against each individual’s initial plasma ATRA level for subjects in the HD-ATRA group. A Spearman correlation coefficient (Corr Coeff) [– 0.415; p = 0.055] suggested that higher plasma ATRA levels were associated with density mask scores that decreased over time. Subjects who were identified as having a significant decrease in their density mask score at 9 months (as shown in left, A) are identified by the black fill, while subjects defined as not having an improved score are shown in white.

 
Tolerability and Toxicity
Adverse events were reported by all but one subject during phase 1 (Table 3 ). Respiratory and GI complaints, as well as fatigue, were common but not specifically associated with drug treatment. All retinoids were associated with higher rates of skin rash and irritation of the mucous membranes, blurred vision, and hypertriglyceridemia. In contrast, only 13-cRA was associated with muscle and joint complaints, hypercholesterolemia, and mild elevations of alkaline phosphatase, while ATRA was associated with transient headaches and mild transaminitis. No serious adverse events were considered to be treatment related, and no subjects died during the study. One death from nasopharyngeal cancer and one death from lung volume reduction surgery were reported afterwards. One participant with a preexisting small nodule was also found to have lung cancer after completion of the study. Twenty-three subjects discontinued participation during the study: on their own (n = 6), due to unrelated intercurrent illness (n = 9), and due to adverse events (n = 6) [headache, n = 2; hyperlipidemia, n = 2; abnormal liver function, n = 1; and depression, n = 1]. Two additional subjects were withdrawn due to potential drug interactions (diltiazem). All of the participants who were withdrawn for adverse events were receiving active drug except for the patient with depression.


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  		Table 3.. Adverse Events Reported During Phase 1*

 
Discussion

Prior to the report by Massaro and Massaro,1 emphysema was considered a progressive and irreversible process. While not all investigators111213 have observed that retinoids will repair emphysematous lung damage, the capacity for ATRA to generate new septa and increase alveolar surface area in the adult lung has been confirmed by other elastase-induced models of emphysema,23 in alveolar remodeling following pneumonectomy,31 and in rodent models of long-term tobacco exposure.4 Unfortunately, none of these models accurately replicate the complex pathophysiology of human emphysema, which also includes prominent changes in basement membrane, pulmonary blood flow, and cell function. Structural and functional changes in human emphysema are also heterogeneously distributed, producing a complex challenge with respect to drug delivery and accurate monitoring of responses. Finally, interspecies- and age-related differences in gene regulation likely exist, as well as considerable differences in the normal rate of lung maturation and the duration of disease.

The FORTE study was therefore designed as a feasibility study to collect preliminary evidence regarding the effects of available retinoids on different measures of human emphysema. The FORTE study was not powered as a definitive trial, which according to our post hoc analysis would have required 224 subjects per group to accurately identify a 10% change in FEV1. Despite this inherent limitation, the study has provided important information. ATRA and 13-cRA were reasonably tolerated in the context of careful screening and monitoring. While no treatment produced an overall and lasting improvement in lung function, treatment-dependent changes in DLCO, QOL, and CT imaging were identified and found to correlate with ATRA blood levels. These results suggest that ATRA may have biological activity in the human lung that warrants further investigation.

The FORTE study employed a placebo-controlled, crossover design with multiple treatment groups in order to address several questions about the type and dose of retinoid to administer. While endogenous ATRA is responsible for promoting lung septation and an increase in alveolar surface area during lung development,578 its therapeutic administration is complicated by its complex metabolism. Oral ATRA induces cytochrome P450 enzymes that significantly reduce maximal blood levels over time.1415 ATRA was therefore administered on an intermittent schedule for only 4 days each week, and at both conventional (1 mg/kg) and higher (2 mg/kg) doses in an attempt to optimize exposure. In a small study1014 with 20 emphysema patients, treatment with ATRA (50 mg/m2) for 3 months had no effect on lung function or CT imaging but significantly reduced plasma matrix metalloproteinase-9 activity. As a result, the FORTE study extended treatment to 6 months, the maximal treatment period allowed by the US Food and Drug Administration. 13-cRA was also considered of interest because it produces stable blood levels, isomerizes to ATRA in plasma and within target cells,3233 and has been shown to upregulate the expression of retinoic acid receptors in lung tissue.34

The frequency and pattern of adverse events matched prior experience with these drugs and often related to both the type and dose of retinoid. Notably, headaches and reversible mild transaminitis were common to both doses of ATRA, while irritation of the skin and mucous membranes, visual changes, and hyperlipidemia were observed in response to all three drugs. Even though the magnitude of side effects was usually mild to moderate, careful toxicity monitoring is warranted in elderly patients with a variety of concurrent illnesses and cardiovascular risk factors.

The placebo-controlled crossover design was employed for several reasons. Assuring participants that they would receive active drug treatment played an important role in recruitment. The initial 6-month phase allowed for a direct placebo-controlled comparison between the different treatments, while the crossover provided a delayed follow-up after drug washout. Information from both of these phases allowed us to identify the reduction in DLCO as an exposure-dependent change related to the time on drug and the measured ATRA blood level. This is a new finding and perhaps the best evidence that retinoid therapy has a physiologic effect on lung function.

In the absence of a true placebo group for the long-term follow-ups, we cannot state conclusively whether this early decrease in DLCO is a measure of lung remodeling or an indicator of drug-related pulmonary toxicity. There are several reasons to suggest the former. First, the DLCO recovered to somewhat higher than baseline levels in the HD-ATRA group after stopping therapy. In addition, administration of HD-ATRA was associated with delayed improvements in health-related QOL and with a subset of individuals who had delayed improvement in CT scores. As with the early decline in DLCO, these later improvements in CT scores correlated with measured ATRA levels, suggesting a relationship between the early disruption of lung function and subsequent evidence of lung repair. Finally, these findings are consistent with studies343536 examining the effects of ATRA on compensatory lung growth following pneumonectomy. Yan et al35 documented histologic evidence of alveolar capillary proliferation after 4 months of ATRA therapy, and this change was associated with a reduction in DLCO.36 The nature of the capillary proliferation, with capillary "dublets," recapitulated a pattern observed during early lung development before compensatory thinning of the alveolar septum resulted in a functional increase in surface area available for gas exchange. As the dogs were killed immediately following their course of ATRA, we are left to speculate whether the dysfunctional capillary bed would have remained without change or continued to remodel, resulting in a delayed improvement in lung function. A similar model in the rat reported a late improvement in alveolar surface area and lung function,34 and it is provocative to speculate that a similar process accounts for the temporal sequence of events observed in the FORTE study (an early decrease in DLCO followed by a delayed recovery and improvement in QOL and CT scores). However, there is currently no convincing evidence to support either conclusion. As a result, the observed changes in DLCO may be due to either drug-related lung toxicity that recovered or a temporal process of lung regeneration.

Overall, the FORTE study did not identify dramatic or lasting improvements in lung function, QOL, or CT measures and cannot be used to support the clinical use of either ATRA or 13-cRA as a treatment for emphysema. If these drugs are active in the human lung, there may be several reasons for the lack of an overall response, including issues related to drug bioavailability. ATRA levels vary widely from one person to another and decline significantly in most subjects over time, even when administered with a drug holiday each week. Administering HD-ATRA produced higher initial and follow-up plasma levels but still did not directly address these issues. 13-cRA, while producing more stable ATRA levels, appears unlikely to achieve effective concentrations at clinically tolerable doses. The IV administration of liposome-complexed ATRA, recently approved as an orphan drug for non-Hodgkin lymphoma, might provide another approach for achieving higher and more stable levels.3738 Liposomal ATRA can achieve 10-fold higher plasma levels that are well sustained over time. Unfortunately, the requirement for IV administration is a significant obstacle to clinical investigation. Synthetic retinoids that exert activity similar to ATRA, but with more stable pharmacokinetics, show promise in animal models and may prove to be of clinical value in the future.439 Another consideration is the combination of ATRA with a stem cell-mobilizing agent. In an interesting model, Ishizawa et al3 reported that both granulocyte-colony stimulating factor and ATRA promote alveolar regeneration, and that the majority of new alveolar septa are formed by circulating stem cells that integrate and differentiate into functional lung tissue. They hypothesize that a lack of circulating stem cells could be a limiting factor in elderly patients. Finally, the goal of the FORTE study needs to be kept in perspective. The FORTE study was a feasibility study and not a definitive clinical trial. While it was possible that a definitive outcome could have resulted, the realistic focus was to identify appropriate drugs, doses, and outcome measures of interest and provide a rational basis for designing more definitive studies in the future.

In summary, administration of ATRA and 13-cRA resulted in frequent, although usually minor, side effects and no overall improvement in pulmonary function or CT imaging. These results do not support the use of retinoids as a clinical treatment for emphysema at this time. However, changes in several outcomes were observed in subjects who achieved high ATRA blood levels, suggesting exposure-dependent biological activity that warrants further investigation. A focus on HD-ATRA, or alternative approaches for achieving higher effective blood levels, should be considered when designing future studies. If our preliminary findings are correct, DLCO, SGRQ, and CT imaging should also be considered as outcome measures of interest for future studies but require additional prospective evaluation and validation.

Appendix

The FORTE study investigators and senior staff from the clinical and coordinating centers; National Heart, Lung, and Blood Institute; and Data and Safety Monitoring Board are listed as follows: Boston University: G. T. O’Connor, MD (Principal Investigator); R. Goldstein, MD; P. Goncalves, RN; N. Kozlowski; A. Theodore, MD; and R. Walter, MD; Columbia University: N. W. Schluger, MD (Principal Investigator); J. Austin, MD; W. S. Blaner, PhD; F. Brogan, MSN, RN; J. D’Armiento, MD, PhD; R. F. Foronjy, MD; P. Jellen, MSN, RN; and S. M. Scharf, MD; PhD; University of California, Los Angeles, Pulmonary: M. D. Roth, MD (Principal Investigator); J. T. Mao, MD; E. C. Kleerup, MD; J. Dermand; and G. Ibrahim; Radiology Core: J. G. Goldin, MbChb, PhD; M. Brown, PhD; J. Ho; and M. McNitt-Gray, PhD; University of California, San Diego: J. W. Ramsdell, MD (Principal Investigator); A. Araneta; P. J. Friedman, MD; M. J. Renvall; and A. L. Ries, MD; University of Pittsburgh: F. Sciurba, MD (Principal Investigator); J. Muindi, MD, PhD; and C. Stewart; University of Minnesota (Data Coordinating Center): J. E. Connett, PhD (Principal Investigator); T. A. Louis, PhD (Johns Hopkins Bloomberg School of Public Health); M. A. Skeans, MS; C. H. Wendt, MD; and H. T. Voelker; Johns Hopkins University: R. A. Wise, MD (Study Chair); Roche Bioscience: Paula Belloni, PhD; National Heart, Lung, and Blood Institute: T. Croxton, MD, PhD (Executive Secretary of the Data and Safety Monitoring Board); J. P. Kiley, PhD (Director, Division of Lung Diseases); G. Weinmann, MD (Project Officer and Director, Airway Biology and Disease Program); and M. Stylianou, PhD (Biostatistician); and Data and Safety Monitoring Board: V. M. Chinchilli, PhD; G. J. Criner, MD; C. K. Daugherty, MD; E. H. Estey, MD; L. Gudas, PhD; D. Lynch, MD; S. E. McGowan, MD; R. M. Senior, MD; and E. Thom, PhD.

Footnotes

Abbreviations: 13-cRA = 13-cis retinoic acid; ATRA = all-trans retinoic acid; DLCO = diffusing capacity of the lung for carbon monoxide; FORTE = Feasibility of Retinoids for the Treatment of Emphysema; HD = high dose; HU = Hounsfield unit; LD = low dose; QOL = quality of life; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TLC = total lung capacity; VA = alveolar volume

Support for the FORTE Study was provided by the National Heart, Lung, and Blood Institute, contracts NO1-HR-96140 (Dr. Connett); NO1-HR-96141–001 (Dr. O’Connor); NO1-HR-96144 (Dr. Ramsdell); NO1-HR-96143 (Dr. Roth); NO1-HR-96145 (Dr. Schluger); and NO1-HR-96142 (Dr. Sciurba).

Hoffman-La Roche Inc. (Nutley, NJ) generously provided the ATRA, 13-cRA, and matching placebo for this study.

Drs. Roth, Connett, and Sciurba have served as consultants to Hoffman-La Roche Inc. related to the field of emphysema research.

No financial or other potential conflicts of interest exist for Drs. D’Armiento, Foronjy, Friedman, Goldin, Louis, Mao, Muindi, O’Connor, Ramsdell, Ries, Scharf, Schluger, Walter, Wendt, and Wise, and Ms. Skeans.

Received for publication February 16, 2006. Accepted for publication May 12, 2006.

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