Study of ACE-1334 to Evaluate the Safety, Pharmacokinetics, Pharmacodynamic Effects, and Efficacy in Participants With Systemic Sclerosis With and Without Interstitial Lung Disease

Sponsor

Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04948554

Collaborator

(none)

210

Enrollment

Locations

Arms

79.5

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This Phase 1b/2 study is designed to assess the safety, efficacy, PK, and PD of ACE-1334 plus SOC in participants with diffuse Systemic Sclerosis (SSc) with or without ILD (Phase 1b) and SSc-ILD (Phase 2).

Condition or Disease	Intervention/Treatment	Phase
Systemic Sclerosis With and Without Interstitial Lung Disease	Drug: ACE-1334 Drug: Placebo	Phase 1/Phase 2

Detailed Description

The Phase 1b study will evaluate the safety and tolerability of ACE-1334 plus standard of care (SOC) administered in 3 multiple-ascending dose (MAD) cohorts by subcutaneous administration in participants with diffuse SSc with or without ILD. In each cohort, ACE-1334 will be explored at 2- and 4-week dosing intervals over 12 weeks, with the potential to extend treatment by up to 40-weeks (per investigator's assessment) and 16 weeks of follow-up, for up to a maximum of 72 weeks (screening, treatment and follow-up).

The Phase 2 study is a double-blind, randomized, placebo-controlled study in which dosing, and frequency of administration will be determined based on the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) data from the Phase 1b study. This study will enroll participants with SSc-ILD who will receive 1 of 2 doses of ACE-1334 or placebo plus SOC. Participation will consist of a 28-day screening period, a 52-week double-blind treatment period, and a 16-week follow-up period. Dose levels and frequency of administration in Phase 2 will be determined based on the safety, tolerability, PK, and PD data from the Phase 1b study. The frequency of administration in Phase 2 will be informed by the Phase 1b study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

210 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

The phase 1b portion of the study will be open label. Eligible participants will receive ACE-1334 plus SOC. The phase 2 portion of the study will be a randomized, double blind placebo-controlled study where eligible participants will be randomly assigned in a 1:1:1 ratio to receive ACE-1334 plus SOC or placebo plus SOC.The phase 1b portion of the study will be open label. Eligible participants will receive ACE-1334 plus SOC. The phase 2 portion of the study will be a randomized, double blind placebo-controlled study where eligible participants will be randomly assigned in a 1:1:1 ratio to receive ACE-1334 plus SOC or placebo plus SOC.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Masking is only applicable to the phase 2 portion of the study. All study personnel (including but not limited to the sponsor, the sponsor's representatives, investigators, study coordinators, nursing staff, and clinical monitors) and all participants will remain blinded to the study treatment assignments.

Primary Purpose:

Treatment

Official Title:

A Phase 1b/2 Open-Label, Multiple-Ascending Dose Study Followed by a Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamic Effects, and Efficacy of ACE-1334 Plus Standard of Care in Participants With Systemic Sclerosis With and Without Interstitial Lung Disease

Actual Study Start Date :

Sep 16, 2021

Anticipated Primary Completion Date :

Dec 1, 2027

Anticipated Study Completion Date :

May 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Arm A Open-label ACE 1334-once every two weeks, Dose 1 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Cohort 1 Arm B Open-label ACE 1334-once every four weeks, Dose 2 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Cohort 2 Arm A Open-label ACE 1334-once every two weeks, Dose 3 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Cohort 2 Arm B Open-label ACE 1334-once every four weeks, Dose 4 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Cohort 3 Arm A Open-label ACE 1334-once every two weeks, Dose 5 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Cohort 3 Arm B Open-label ACE 1334-once every four weeks, Dose 6 + SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Phase 2 Arm A (Dose 1) Double-blind/placebo-controlled ACE 1334-once every x weeks xx mg/kg +SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Experimental: Phase 2 Arm B (Dose 2) Double-blind/placebo-controlled ACE 1334-once every x weeks yy mg/kg +SOC	Drug: ACE-1334 ACE-1334 is a recombinant homodimeric Fc fusion protein comprising of the extracellular domain (ECD) of the human TGF-βRII, linked to a modified human Fc domain of IgG1
Placebo Comparator: Phase 2 Placebo + SOC Placebo to match ACE-1334 + SOC	Drug: Placebo Placebo: matching placebo

Outcome Measures

Primary Outcome Measures

Part 1/Phase 1b: To evaluate the incidence of Treatment-Emergent Adverse Events (safety and tolerability) of ACE-1334 plus SOC in participants with SSc [From baseline to Week 12]
Part 2/Phase 2 Treatment period: To evaluate the effect on forced vital capacity (FVC) in participants with SSc-ILD treated with placebo plus SOC compared with ACE-1334 plus SOC. [From baseline to 52 weeks]
Assessment of the annual rate of decline in FVC, which is the total amount of air exhaled during lung function testing.

Secondary Outcome Measures

Part 1/Phase 1b: To assess incidence of Treatment-Emergent Adverse Events (long-term safety and tolerability) of ACE-1334 plus SOC in participants with SSc. [From baseline to Week 52]
Part 1/Phase 1b: To characterize the PK profile- Area under the concentration-time curve over a dosing interval (AUCtau) of ACE-1334 in participants with SSc [From baseline up to Week 12]
Part 1/Phase 1b: To characterize the PK profile- Maximum observed concentration (Cmax) of ACE-1334 in participants with SSc [From baseline up to Week 12]
Part 1/Phase 1b: To characterize the PK profile- Time to Cmax (Tmax) of ACE-1334 in participants with SSc [From baseline up to Week 12]
Part 1/Phase 1b: To characterize the PK profile- Observed concentration at the end of a dosing interval (Ctrough) of ACE-1334 in participants with SSc [From baseline up to Week 52]
Part 1/Phase 1b: To characterize the effects of multiple ascending doses of ACE 1334 plus SOC on TGF- β responsive gene expression in skin [Up to Week 12]
Part 1/Phase 1b: To characterize the effects of multiple ascending doses of ACE 1334 plus SOC on surfactant protein-D (SP-D), a marker of lung injury [Up to Week 52]
Part 2/Phase 2 Treatment Period: To determine the proportion of participants who achieve a response using Composite Response Index in Systemic Sclerosis (CRISS) [At week 52]
The CRISS was developed as a composite index consisting of 5 domains (modified Rodnan Skin Score, FVC, Health Assessment Questionnaire-Disability Index, Patient Global Assessment, and Physician Global Assessment) CRISS is an assessment of the probability of improvement on a 0.0 to 1.0 scale for each participant, 0.0 represents no improvement and 1.0 is a marked improvement.
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on disease burden endpoints in participants with SSc-ILD compared with placebo plus SOC [From baseline to week 52]
Assessment of the change in the extent of fibrosis as determined by High Resolution CT scan.
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on the modified Rodnan Skin Score (mRSS) [From baseline to Week 52]
The mRSS consists of an evaluation of skin thickness rate by clinical palpation using a scale of 0 to 3 (0=normal skin; 1=mild thickness; 2=moderate thickness; 3=severe thickness) for each of the 17 surface anatomical areas of the body.
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC in diffusion capacity of the lung for carbon monoxide (DLCO) from baseline [From baseline to Week 52]
The DLCO assessments will be performed according to the pulmonary function assessment manual.
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on change from baseline on the St. George's Respiratory Questionnaire (SGRQ) [From baseline to Week 52]
The St. George's Respiratory Questionnaire measures health status in participants with chronic airflow limitation. It comprises 2 parts that cover 3 domains (symptoms, activities, and impacts) with scores that range from 0 (no impairment) to 100 (maximum impairment).
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on the Scleroderma Health Assessment Questionnaire (SHAQ) [From baseline to Week 52]
The SHAQ is composed of the standard Health Assessment Questionnaire and additional visual analog scales to measure symptoms specific to scleroderma and overall disease severity.
Part 2/Ph 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on change from baseline on the Living with Idiopathic Pulmonary Fibrosis (L-IPF) Questionnaire [From baseline to Week 52]
The Living with Idiopathic Pulmonary Fibrosis (L-IPF) questionnaire is designed to assess symptoms, disease impact, and health-related quality of life for patients with idiopathic pulmonary fibrosis (IPF), which shares many common features with SSc-ILD.
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on change from baseline on the Patient Global Assessment [From baseline to Week 52]
The Patient Global Assessment is a self-administered assessment and represents the participant's overall assessment of his or her current SSc status on a scale of 0 (excellent) to 10 (extremely poor).
Part 2/Phase2 Treatment Period: To assess the effects of ACE-1334 plus SOC on change from baseline on the Physician Global Assessment [From baseline to Week 52]
The Physician Global Assessment is to be completed on the basis of examination and overall assessment of the participant after all other study procedures have been completed. The physician's assessment of the participant's SSc status will be scored on a scale of 0 (excellent) to 10 (extremely poor).
Part 2/Phase 2 Treatment Period: To assess the effects of ACE-1334 plus SOC on the time to clinical worsening [From baseline to Week 52]
Defined as the time from randomization to the time of one of the following events (whichever occurs first) during the 52-week double-blind treatment period: All-cause death Decline in percent-predicted FVC ≥ 10% relative to baseline 20% increase in mRSS and an increase in mRSS of ≥ 5 points Occurrence of a pre-defined SSc-related complication
Part 2/Phase 2 Treatment Period: To evaluate the incidence of Treatment-Emergent Adverse Events (safety and tolerability) of ACE-1334 plus SOC in participants with SSc-ILD [From baseline to Week 52]
Part 2/Phase 2 Treatment Period : To assess Population PK (apparent total clearance [CL/F]) of ACE-1334 in participants with SSc-ILD [From baseline to Week 52]
Part 2/Phase 2 Treatment Period: To assess Population PK (apparent volume of distribution [V/F]) of ACE-1334 in participants with SSc-ILD [From baseline to Week 52]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent consistent with International Council for Harmonisation Good Clinical Practice guidelines and local laws signed prior to entry into the study and any study-related procedures
Male or female participants aged ≥ 18 years at the time of informed consent
For both the Phase 1b and 2 portions of the study, participants must have SSc (with or without ILD), as defined using the American College of Rheumatology/European League Against Rheumatism criteria

For the Phase 1b study, participants must have diffuse SSc (with and without ILD)
For the Phase 2 study, participants must have SSc-ILD. Presence of ILD will be confirmed by central reading of the screening high-resolution computed tomography (HRCT)

SSc disease onset (defined by first non-Raynaud symptom) must be within 60 months of screening
If participant is on a non-excluded immunosuppressive therapy (e.g. mycophenolate, methotrexate, azathioprine, etc.) the dose should be stable for > 6 months at the time of screening
FVC ≥ 50% of predicted normal at screening
Presence of at least one of the following at screening:

C-reactive protein levels at screening of ≥ 6 mg/L
Erythrocyte sedimentation rate ≥ 28 mm/hr
Platelet count ≥ 330 × 10^9/L (33,000/μL)

mRSS at screening of ≥ 15
DLCO (corrected by hemoglobin at screening): ≥ 40% to ≤ 89%
Women of childbearing potential must:

Have 2 negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting investigational product, during the study (including dose interruptions), and for 17 weeks (119 days) after discontinuation of study treatment
Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 17 weeks (119 days) after the last dose of study treatment

Male participants must:

Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 17 weeks (119 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
Refrain from donating blood or sperm for the duration of the study and for 17 weeks (119 days) after the last dose of study treatment

Must agree to not participate in any other study of investigational drugs/devices while enrolled in this study

Exclusion Criteria:

Participant with SSc-pulmonary arterial hypertension (PAH) (except those participants with mild PAH on up to 2 oral drugs and mean pulmonary arterial pressure < 30 mmHg or low risk by risk calculator)
Participant with airway obstruction (pre-bronchodilator forced expiratory volume in the first second/FVC ˂ 0.7)
In the opinion of the investigator, other clinically significant pulmonary abnormalities (such as obstructive lung disease, asthma, etc.)
Other investigational therapy received within 1 month or 6 half-lives (whichever is greater) prior to the Screening Visit
Prior exposure to ACE-1334 or other TGF-β antibodies or any TGF-β family targeted biologic or hypersensitivity to the components of ACE-1334
Hypersensitivity to placebo or any of its components (Phase 2 only)
Previous hematopoietic stem cell transplantation (HSCT) or HSCT planned within the next year
Major surgical procedures planned during the study period
Oral prednisone or equivalent > 10 mg/day
Participant with history of gastric antral vascular ectasia or gastrointestinal bleed
On anticoagulation therapy (such as prophylaxis anticoagulation, warfarin, direct thrombin inhibitors or other including low molecular weight subcutaneous or intravenous therapeutic heparin), or antiplatelet therapy other than daily aspirin for cardiovascular protection. Use of fish oil supplements within 2 weeks prior to randomization.
History of any other medical condition that might interfere with a participant's ability to participate in the study
Active clinically significant viral, bacterial, or fungal infection, or any episode of infection requiring hospitalization within 4 weeks prior to screening.
Use of cyclophosphamide ≤ 6 months from screening
Use of nintedanib or pirfenidone ≤ 28 days from screening
Recent scleroderma renal crisis < 6 months before screening
Use of tocilizumab ≤ 2 months from screening
Hemoglobin < 10 g/dL at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck Medical Center of University of Southern California	Los Angeles	California	United States	90033
2	Central Florida Pulmonary Group PA	Orlando	Florida	United States	32803
3	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
4	West Tennessee Research Institute	Jackson	Tennessee	United States	38305
5	Dr Anil Dhar Professional Medicine Corporation	Windsor	Ontario	Canada	N8X 5A6