Protocol and rationale for a randomised, double-blind, placebo-controlled phase 3 trial of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with idiopathic pulmonary fibrosis: ALOFT-IPF

Abstract

Introduction

Idiopathic pulmonary fibrosis (IPF) is associated with progressive loss of lung function and poor prognosis. There remains a need for novel therapies for patients with IPF. Admilparant, an oral lysophosphatidic acid receptor 1 antagonist, slowed lung function decline and was well tolerated in a phase 2 trial when administered 60 mg two times per day in patients with IPF over 26 weeks. This report describes the design and rationale of the pivotal ALOFT-IPF phase 3 trial, which aims to further evaluate admilparant for patients with IPF.

Methods and analysis

ALOFT-IPF, a global, phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial, completed enrolment on 5 September 2025. Adults (≥40 years) with IPF were randomised to receive admilparant 60 mg or 120 mg or placebo (1:1:1) orally, two times per day for ≥52 weeks. Inclusion criteria included IPF diagnosis within 7 years, percentage of predicted forced vital capacity ≥40% and percentage of predicted diffusing capacity of the lung for carbon monoxide ≥25%. Background antifibrotic treatment was permitted. Randomisation was stratified by antifibrotic therapy and sex. A two-cohort design was used to assess the safety of admilparant 120 mg. Cohort 1 (n=60), a single-blind design, evaluated safety and tolerability of admilparant; the primary endpoint was the number of spontaneous syncopal episodes after 4 weeks. Based on data evaluation, continuation of the trial was permitted without change and recruitment into cohort 2 initiated. Cohort 2 (n=1191) has a registrational, double-blind design to evaluate the efficacy, safety and tolerability of admilparant compared with placebo; the primary endpoint is absolute change in forced vital capacity from baseline at week 52. The trial is estimated to complete in October 2026.

Ethics and dissemination

This trial is being conducted in accordance with the protocol and international guidelines, applicable local laws, regulations and requirements.

Trial registration number

NCT06003426.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Idiopathic pulmonary fibrosis (IPF) is a debilitating disease associated with progressive loss of lung function and, although approved antifibrotics slow lung function decline, they do not halt disease progression and are often not well tolerated. There remains a substantial unmet medical need for patients with IPF. A phase 2 trial showed that the novel lysophosphatidic acid receptor 1 (LPA₁) antagonist, admilparant, slowed lung function decline and was well tolerated in patients with IPF.

WHAT THIS STUDY ADDS

• The global, phase 3, multicentre, randomised, double-blind, placebo-controlled ALOFT-IPF trial aims to further evaluate admilparant as a treatment option for patients with IPF. The treatment period will extend beyond 52 weeks to increase the likelihood of clinically meaningful benefits beyond the primary endpoint of forced vital capacity, which is a standard measure of disease progression.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• The ALOFT-IPF trial aims to assess the efficacy and safety of admilparant, a novel oral LPA₁ antagonist and provide insight into the IPF patient population and the impact of treatment with the novel oral LPA₁ antagonist. Results of the trial have the potential to affect current treatment practice and address an unmet need in this patient population.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing form of interstitial lung disease (ILD) with no identifiable cause and a poor prognosis.^1–3 IPF is associated with worsening dyspnoea, cough, progressive loss of lung function and deterioration in health-related quality of life.^2–5 Median survival for patients with untreated IPF is approximately 3–5 years from diagnosis.^6–8

Until recently, IPF treatment options were limited to two approved antifibrotic drugs, nintedanib and pirfenidone. Although these drugs slow lung function decline, they do not stop disease progression and may be poorly tolerated.^9–13 Gastrointestinal adverse effects, particularly diarrhoea with nintedanib and nausea with pirfenidone, are common, and pirfenidone may also cause photosensitivity and rash.^{9 10 13} In October 2025, the preferential inhibitor of phosphodiesterase 4B, nerandomilast, received US Food and Drug Administration approval for the treatment of IPF on the basis of reduced forced vital capacity (FVC) decline compared with placebo and adequate safety profile in phase 3.^{14 15} Several other molecules targeting the fibrotic pathways are also in development for IPF,¹⁶ including treprostinil, an inhaled prostacyclin agonist, which met its phase 3 primary endpoint in one study, with a smaller decline in FVC than placebo over 52 weeks.^{17 18} Despite these advances, there remains an unmet need for safe, well-tolerated and effective therapy for IPF that delays disease progression and reduces mortality.

Lysophosphatidic acid (LPA) mediates multiple basic cellular functions associated with wound healing, including survival/apoptosis, proliferation, migration and contraction, and in doing so can regulate normal-to-aberrant wound repair (fibrosis), characterised by excessive deposition of collagen and extracellular matrix.^19–21 LPA₁ belongs to a family of G protein-coupled receptors activated by LPA, and LPA-LPA₁ receptor signalling plays a central role in the pathogenesis of fibrotic lung disease.^19–22 LPA₁ receptor antagonism thus presents itself as a therapeutic strategy for progressive fibrosing diseases such as IPF.

Admilparant (previously known as BMS-986278), a potent, selective, novel small-molecule LPA₁ antagonist, is an orally administered investigational product being developed for the treatment of patients with IPF and progressive pulmonary fibrosis (PPF).²³ In the phase 2 NCT04308681 (IM027040) trial in patients with lung fibrosis, admilparant showed favourable safety and efficacy, both as monotherapy and in combination with antifibrotic therapy.²⁴ In the cohort of patients with IPF, admilparant 60 mg two times per day resulted in an overall relative reduction of 54% in the rate of decline in percentage of predicted FVC (ppFVC) compared with placebo over 26 weeks. Blood pressure (BP) monitoring criteria were prespecified in the trial, and although post-dose reductions in systolic BP were observed on day 1 of 60 mg admilparant two times per day dosing, they were self-limiting. These results support the continued development of admilparant, and phase 3 studies have been initiated for patients with IPF (NCT06003426; Trial IM027068) and PPF (NCT06025578; Trial IM0271015).

Here, we present the protocol for ‘An LPA₁ antagonist for pulmonary Fibrosis Trial (ALOFT)-IPF’ (NCT06003426), a phase 3 randomised, double-blind, placebo-controlled clinical trial investigating the efficacy, safety and tolerability of admilparant in patients with IPF for ≥52 weeks.

Methods and analysis

Trial design

ALOFT-IPF is a phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial that began enrolment on 14 September 2023, across >30 countries and >400 clinical sites. Enrolment completed on 5 September 2025, and the trial is ongoing; estimated to complete in October 2026. In ALOFT-IPF, patients with IPF were randomised to admilparant 60 mg or 120 mg, or placebo (1:1:1), two times per day orally for ≥52 weeks. Patients were allowed to continue nintedanib or pirfenidone antifibrotic therapy for IPF, and randomisation (conducted via interactive response technology) was stratified by concomitant IPF therapy (pirfenidone vs nintedanib vs none) and sex (male vs female). The trial uses a two-cohort design (figure 1).

Figure 1. Trial design. *Stratified by concomitant use of approved antifibrotic therapy (pirfenidone vs nintedanib vs none) and sex (male vs female). †Titration period is intended to be completed in 7–16 days with a minimum of 2 consecutive days of dosing required between titration visits. ‡Treatment period is a minimum of 52 weeks and up to approximately 3 years, except for patients in European Economic Area countries, who can participate for a maximum of 2 years. §Schedule for the treatment period for both cohorts includes an approximate 7-day dose titration period from day 1 followed by the assigned treatment arm dose, with visits Q6W up to week 52 and Q12W from week 52 to EOT. ‖Primary endpoint analysis, that is, the date when the last patient completes their 52-week treatment visit. This visit date marks the completion of the primary endpoint for the study and is crucial for data collection and analysis. ¶EOT per the schedule of activities. The period from week 52 to EOT is variable for participants who continue treatment and remain double-blinded throughout the trial. **Follow-up visit is scheduled 28 days after the last dose of trial treatment. BID, two times per day; EOT, end of treatment; Q×W, every × weeks.

Cohort 1 had a single-blind design with only the sponsor unblinded to make informed strategic decisions. As cohort 1 was not a registrational part of the main study, sponsor review of data did not impact study conduct or integrity. Cohort 1 enrolled patients first and randomised 60 eligible patients with IPF. Before cohort 2 was initiated, an internal review committee (IRC), composed of unblinded sponsor committee members independent of the trial team, reviewed available data from the ALOFT-IPF and ALOFT-PPF trials. The IRC closely monitored spontaneous syncopal events in cohort 1 from visit 4 (day 7) to visit 5 (day 29); defined as transient loss of consciousness caused by inadequate cerebral blood flow and oxygenation, and associated with spontaneous recovery. The IRC determined that the conditions for continuing the trial without modification were met and cohort 2 was initiated. Patients assigned to cohort 1 could continue treatment beyond visit 5, remaining in their assigned cohort. Cohort 2 (n=1191) is registrational with a double-blind design, whereby the sponsor, investigators, patients, families and caregivers remain blinded to treatment assignments. An external data monitoring committee periodically monitors accumulating efficacy and safety data, including treatment discontinuations due to adverse events related to low BP.

Both cohorts include the same three periods, trial assessments (with few exceptions) and duration (figure 1). The screening period was approximately 6 weeks to provide informed consent and determine eligibility. The treatment period consists of a 7-day titration phase and a post-titration phase of at least 52 weeks (for primary endpoint evaluation), up to approximately 2 years for patients in European Economic Area countries and 3 years for other countries. During titration visits 1–3 (week 1), patients receive blinded admilparant or placebo two times per day, with admilparant dose increased incrementally from 10 mg (visit 1; day 1) to 30 mg (visit 2; day 3) to 60 mg (visit 3; day 5). From visit 4 (day 7) through end of treatment, patients either continue treatment (admilparant 60 mg two times per day or placebo) or initiate admilparant 120 mg two times per day or placebo per their assigned treatment arm. At visits 1–5, seated serial systolic BP assessments, pulse rate and orthostatic (supine to standing position) BP assessments are collected to determine whether patients can continue with dosing or if extended onsite BP monitoring is required. After visit 5 (day 29), visits occur every 6 weeks up to week 52 (primary endpoint visit), and then every 12 weeks to end of treatment. Patients return to the trial site for efficacy, safety and patient-reported outcome assessments. Patients in cohort 2 complete self-reported assessments using an electronic device. In addition, samples for pharmacokinetic and biomarker assessments are collected. Safety assessments include 12-lead ECG, physical examination, vital signs, seated BP and adverse events. Efficacy assessments include spirometry, diffusing capacity of the lung for carbon monoxide (DLco) and 6 min walk test (6MWT; cohort 2 only). A safety follow-up visit is scheduled approximately 28 days after the last dose.

Trial population

The trial enrolled adults ≥40 years of age with a diagnosis of IPF within 7 years and verification of usual interstitial pneumonia (supported by centrally read chest CT at screening), ppFVC ≥40%, forced expiratory volume in 1 s (FEV₁)/FVC ≥0.7, and single-breath, haemoglobin-corrected percentage of predicted DLco ≥25% at screening. Patients on a stable dose (≥90 days before screening) of background antifibrotic treatment were eligible.

Patients were excluded if they had ILD associated with a known cause, history of stroke or transient ischaemic attack within 3 months before screening, exhibited symptoms of heart failure at rest, or had either a current malignancy, a previous malignancy with <2 years free of recurrence or a biopsy suspicious for malignancy. Use of systemic corticosteroids equivalent to prednisone >15 mg/day within 4 weeks of screening was not permitted or during the study.

Key patient eligibility criteria are provided in box 1; complete criteria are provided in online supplemental box 1.

Box 1. Key inclusion and exclusion criteria.

Inclusion criteria

Patients are eligible to be included in the trial only if all of the following criteria apply:

• Signed written informed consent.

• ≥40 years of age at the time of signing the ICF.

Type of patient and target disease characteristics

• Diagnosis of IPF within 7 years before screening, supported by centrally read chest HRCT at screening and verification of UIP.

• ppFVC ≥40% at screening.

• FEV₁/FVC ≥0.7 at screening.

• Single-breath, haemoglobin-corrected, ppDL_CO≥25% at screening.

• If on pirfenidone or nintedanib, patients must have been receiving a stable dose for at least 90 days before screening. If not currently on pirfenidone or nintedanib, patients must not have received either of these medications within 28 days before screening.

• Investigator has considered all available IPF treatment options before obtaining informed consent.

Exclusion criteria

Patients are excluded from the trial if any of the following criteria apply:

Medical conditions

• ILD associated with known primary causes.

• Emphysema ≥50% on HRCT assessed by a central reader, or the extent of emphysema is greater than the extent of fibrosis according to reported results from the most recent HRCT.

• Acute exacerbation of pulmonary fibrosis within 4 weeks before or during screening.

• Clinically significant non-parenchymal lung disease at screening.

• Clinically significant respiratory tract infection within 4 weeks before screening or during screening; for prior SARS-CoV-2 infection, symptoms must have completely resolved without sequelae.

• History of stroke or transient ischaemic attack within 3 months before screening.

• Exhibit symptoms of heart failure at rest.

• History of lung reduction surgery or lung transplant (being on transplantation list is allowed).

• Known PAH that requires multidrug therapy.

• Cigarette smoking (including e-cigarettes) within 3 months before day 1.

• History of persistent or active post-micturition/defecation and anamnestic known syncope.

• History of persistent or active postural orthostatic tachycardia syndrome.

• Symptomatic valvular heart disease including mitral stenosis, aortic stenosis and bicuspid aortic valve.

• Aortic dissection requiring surgery or intervention.

• Patients who have: (1) a current malignancy; (2) a previous malignancy with <2 years free of recurrence; (3) a biopsy that is suspicious for malignancy and the possibility of malignancy cannot be reasonably excluded after additional clinical, laboratory or other diagnostic evaluations.

• Symptomatic bradycardia or symptomatic second-degree or any uncorrected third-degree heart block.

Trial endpoints

Endpoints will be analysed separately for each cohort. Endpoints are detailed in full in online supplemental box 2.

For cohort 1, the primary endpoint is the number of patients experiencing spontaneous syncopal events in the admilparant 120 mg and placebo arms during from visit 4 to visit 5. The secondary endpoint is the discontinuation rate due to any adverse events related to low BP and safety assessments of admilparant 60 and 120 mg two times per day compared with placebo throughout the study.

For cohort 2, the primary endpoint is absolute change in FVC (in mL) from baseline at week 52. Key secondary endpoints include time to first disease progression event, from baseline through the primary endpoint visit, in at least one of the following: absolute ppFVC decline of ≥10% from baseline; acute exacerbation of pulmonary fibrosis; respiratory-related hospitalisation; and all-cause mortality. Further, changes in Living with Pulmonary Fibrosis Questionnaire (L-PF) cough domain score, walking distance measured using the 6MWT and L-PF dyspnoea domain score from baseline at week 52 are included as key secondary endpoints.

Sample size determination

The sample size determination for cohort 1 (n=60) was based on empirical assessment without formal statistical consideration to compare the number of patients experiencing syncopal events in the admilparant 120 mg and placebo arms.

Cohort 2 (n=1125) was designed to ensure robust evidence, powered at a one-sided 1% significance level to meet regulatory expectations for substantial evidence of efficacy in a single phase 3 trial. Formal hypothesis testing will be performed with type I error controlled at the one-sided 2.5% significance level. Sample size computation assumed that the treatment difference to detect is a change in FVC of 92 mL from baseline, and the SD of the mean change in FVC is 325 mL, based on data from the IM027040 phase 2 trial and other pivotal trials.^{11 12 24} To control the family-wise one-sided type I error at α=0.025 in testing the primary endpoint and key secondary endpoints, a graphical approach is applied as presented in online supplemental figure 1.^{25 26} As there are two additional key secondary endpoints tested outside of the EU (changes in L-PF cough and dyspnoea domain scores), two testing strategies are used, both with two-thirds of the overall type I error (0.0167) allocated to test the primary endpoint for admilparant 120 mg and one-third (0.0083) allocated to test the primary endpoint for admilparant 60 mg. With the proposed graphical approach, a sample size of 1125 patients, randomised 1:1:1 to the three arms (375 patients per arm), ensures a power of over 90% to detect statistical significance for either H1 or H2 (primary endpoint) in online supplemental figure 1.

Statistical analysis

Trial endpoints will be analysed and reported by relevant analysis populations for each cohort separately (online supplemental box 2). There will be no formal testing for cohort 1, and all data will be summarised using descriptive statistics. In cohort 2, estimands are defined for the primary and key secondary endpoints (online supplemental box 2).²⁷ The primary endpoint, absolute change in FVC (in mL) from baseline at week 52, will be analysed using mixed model repeated measures (MMRM) including FVC (in mL) change as response, time, treatment, stratification factors, baseline FVC, age and height and interactions of time and these covariates as model effects. Consistency of treatment effect will be explored in subgroup analyses. For key secondary endpoints, time-to-event variables will be analysed by Kaplan-Meier methods, using stratified log-rank test to determine treatment difference, and a Cox proportional hazards model to estimate HRs. Change from baseline in continuous endpoints will be analysed using MMRM. Sensitivity (based on the assumption of informative censoring) and supplementary (using different strategies for intercurrent events) analyses will also be performed. Binary secondary endpoints will be analysed using the Cochran-Mantel-Haenszel test stratified by the randomisation stratification factors. Safety data will be summarised using descriptive statistics.

Patient and public involvement

Input into the trial design was obtained from patients living with pulmonary fibrosis through Patient Voice interviews via a patient advisory board. The trial design was thought to be realistic for this population, but to help minimise the potential burden of participation, patients recommended decentralised capabilities (eg, telemedicine or remote visits); reimbursement for trial-related visit expenses; optional use of the trial site supplemental oxygen (to minimise patients’ concerns about running low on oxygen); and letter and colour labels for the trial medication.

Discussion

Rationale for trial design

The trial included an initial cohort 1 to assess the safety and tolerability of admilparant 120 mg two times per day in a small group of participants to establish if the trial could proceed as planned.

In this trial, a placebo-control group is being utilised to confirm the clinical benefit and safety profile of admilparant observed in phase 2.²⁴ Equal and random assignment of patients to admilparant 60 mg, 120 mg and placebo allows truly trending events in any one group to be identified. The treatment period extends beyond 52 weeks to increase the chances of assessing potential benefits of admilparant in additional clinical measures beyond FVC, for example, respiratory-related hospitalisation, acute exacerbations and patient-reported outcomes.

Rationale for dose selection

To determine the admilparant dose, an exposure-response model was developed following NCT04308681 (IM027040) data analysis.²⁴ Model simulations predicted meaningful improved benefit in FVC for patients administered admilparant 120 mg two times per day compared with admilparant 60 mg two times per day, and support testing the higher dose in phase 3 trials. Additionally, as asymptomatic reductions in BP were noted with first dose administration of admilparant at 60 mg, pharmacokinetic/pharmacodynamic modelling and simulation was evaluated and suggested dose titration should be implemented to reduce potential risk of post-dose reductions in systolic BP. Spontaneous syncope, a clinically meaningful indicator of hypotension, was closely monitored in cohort 1 to determine whether to proceed with the admilparant 120 mg dose in cohort 2.

Rationale for endpoints

FVC is a robust clinical measurement that is a standard for the determination of disease progression, whereas categorical decrements of FVC are powerful predictors of mortality,²⁸ and was therefore selected as the primary endpoint for cohort 2. The secondary endpoints are well suited to reliably assess efficacy and safety, align with expectations of regulatory authorities and are similar to those in other IPF trials.^{11 12 23 28–31} Change in L-PF cough and dyspnoea domain scores are defined as key secondary endpoints for non-EU health authority submissions,²⁸ but are secondary endpoints only for EU health authority submissions due to differences in regulatory requirements. As noted in a recent concept paper drafted by the European Medicines Agency to guide clinical investigation of medicinal products for IPF, these endpoints may be more important for future trials.³² Genetic variation may impact patients’ responses to trial intervention and affect the pharmacokinetic profile of admilparant; therefore, the presence of polymorphism variants, and the association between IPF genetic risk polymorphisms and clinical response to admilparant will be explored. Additionally, biomarkers of lung fibrosis and inflammation may be explored to determine changes in response to admilparant.

Potential study limitations

This study only tests admilparant in addition to standard of care treatment, and will not provide information on the role of admilparant as either monotherapy or combination therapy in newly diagnosed patients.

Conclusion

ALOFT-IPF is a phase 3 trial designed to assess the safety and efficacy of treatment with admilparant, an oral LPA₁ antagonist, on FVC, disease progression and quality of life for up to 3 years in patients with IPF. Enrolment commenced 14 September 2023 and was completed on 5 September 2025. The trial is ongoing and estimated to complete in October 2026.

Data availability statement

No data are available.