Design of CONQUEST, a novel, randomized, placebo-controlled, Phase 2b platform clinical trial to investigate new treatments for patients with early active systemic sclerosis with interstitial lung disease

Abstract

Objective: Safe, effective therapies are urgently needed for patients with systemic sclerosis. However, clinical trial recruitment is challenging given the limited number of people with systemic sclerosis and further restrictions imposed by eligibility criteria. Innovative approaches are needed to accelerate development of new therapies. This article describes the rationale and trial design for CONQUEST (NCT06195072), a novel platform clinical trial sponsored by the Scleroderma Research Foundation, a not-for-profit organization.

Methods: CONQUEST is a multicentre, double-blind, randomized, placebo-controlled, Phase 2b platform trial evaluating the efficacy, safety and pharmacodynamics of multiple investigational products to treat early active systemic sclerosis with interstitial lung disease versus placebo. The primary objective is to evaluate change from baseline to Week 52 in forced vital capacity (mL). Secondary objectives include evaluating changes from baseline to Week 52 in high-resolution computed-tomography-assessed lung involvement and dyspnoea, and overall treatment response (measured using the revised composite response index in diffuse systemic sclerosis score in participants with diffuse cutaneous systemic sclerosis).

Results: Patients will be enrolled across more than 150 centres in over 25 countries. Recruitment started on 15 April 2024.

Conclusion: As the first platform clinical trial in the rheumatology field, CONQUEST aims to meaningfully accelerate the development of new therapies for early active systemic sclerosis. Depending on regimen-specific results, trial data could be used to plan and design a Phase 3 trial or may be used alone or together with another registrational trial to establish substantial evidence of effectiveness and safety. The first molecules to be studied, amlitelimab and nerandomilast, both have a strong scientific rationale to modify underlying disease processes in systemic sclerosis.

Clinicaltrialsgov: Platform Clinical Study for Conquering Scleroderma (CONQUEST); NCT06195072; https://www.clinicaltrials.gov/study/NCT06195072.

Keywords: Systemic sclerosis; amlitelimab; interstitial lung disease; nerandomilast; platform trial; randomized clinical trial; scleroderma; study design.

Figure 1.

Benefits of the platform clinical trial approach.

Figure 2.

Potential mechanisms of action of amlitelimab and nerandomilast in SSc-ILD. In line with its effects on OX40–OX40L signalling, amlitelimab is proposed to exert its effects in T cells^- and B cells^,, (see Figure 3 for more information). In line with other PDE inhibitors, nerandomilast is proposed to exert its effects in macrophages,^, T cells, B cells,^, endothelial cells, epithelial cells (via effects on SP-D release)^, and fibroblasts/myofibroblasts^,, (see Figure 4 for more information). PDE: phosphodiesterase; SP-D: surfactant protein D; SSc-ILD: systemic sclerosis with interstitial lung disease; Th: T helper cell.

Figure 3.

Amlitelimab detailed mechanism of action. Due to the important role of lymphocyte and fibroblast interplay in SSc, costimulatory pathways are an attractive target, and evidence supports the OX40–OX40L costimulatory pathway as a target for SSc.^– OX40–OX40L signalling plays a role in controlling the extent of T-cell priming following antigen recognition, typically promoting T-cell proliferation, survival, and context-dependent Th1, Th2 and Th9 skewing and cytokine release. OX40–OX40L signalling also promotes germinal centre formation and humoral immunity via Tfh survival and helper function to B cells. Amlitelimab is a fully human, non-depleting, non-cytotoxic anti-OX40L monoclonal antibody, which is administered by subcutaneous injection.^, Amlitelimab binds to OX40L on APCs to prevent OX40–OX40L interaction^, and targets upstream antigen-dependent T-cell responses. Amlitelimab binds to OX40L without cytotoxicity or any known target-cell activation^, and inhibits T-cell-dependent inflammation without depleting essential T-cell immunity.^, Given the current knowledge of OX40–OX40L in SSc,^,, amlitelimab may be an attractive therapeutic in SSc. APC: antigen-presenting cell; OX40L: OX40 ligand; SSc: systemic sclerosis; Tfh: T follicular helper cell; Th: T helper cell.

Figure 4.

Nerandomilast detailed mechanism of action Three key pathways in the pathophysiology of SSc are vasculopathy, immune dysregulation (involving inflammation and autoimmunity) and fibrosis (involving excessive ECM production and deposition.^– Nerandomilast (BI 1015550) is an orally administered preferential PDE4B inhibitor that increases levels of cyclic adenosine monophosphate, leading to immunomodulatory and antifibrotic properties, as seen in preclinical studies of nerandomilast and other PDE4 inhibitors.^, By binding to PDE4B in T cells, B cells and macrophages, nerandomilast and other PDE4B inhibitors target immune dysregulation, reducing the release of proinflammatory cytokines and increasing the synthesis of anti-inflammatory cytokines.^–, Nerandomilast also inhibits progressive fibrosis by blocking fibroblast proliferation, myofibroblast differentiation and ECM synthesis.^,, Note that these actions of PDE4 inhibition are not specific to the lung but also apply to other organs affected by SSc, e.g. skin^, or gastrointestinal (not published, data on file). ECM: extracellular matrix; PDE4B: phosphodiesterase 4B; SSc: systemic sclerosis.

Figure 5.

CONQUEST trial design: (a) Trial overview. (b) How sharing the placebo group reduces the number of patients needed for each regimen. (c) Randomization of oral versus subcutaneous treatments. FVC: forced vital capacity; ILD: interstitial lung disease; SSc: systemic sclerosis.