ALlogeneic Cardiosphere-derived Stem Cells (CDCs) for Pulmonary Hypertension therApy
Condition: Pulmonary Arterial Hypertension (PAH)
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Study type: Interventional
Phase: Phase 1

Summary: 
      Pulmonary Arterial Hypertension or PAH is a progressive condition for which there is no cure.
      Even with substantial pharmacologic advances in the modern treatment era, survival still
      remains unacceptably poor, as reported in large PAH registries. Preclinical studies suggest
      that the administration of allogeneic CDCs have the potential to reduce adverse arteriolar
      remodeling in PAH which was the basis for the approved investigational new drug (IND). The
      use of CDCs as an adjunctive therapy in patients comprising 4 sub-groups of patients with PAH
      in which inflammation and immune dysfunction are key pathophysiologic drivers of PAH.
    

Detailed description: 
      Patients with IPAH, HPAH, PAH-CTD and PAH-HIV meeting all inclusion and no exclusion criteria
      will be enrolled. An open label phase 1a study (evaluating dosage and safety) will be
      conducted. This will followed by a randomized double blind placebo controlled Phase 1b study
      after Data Safety and Monitoring Board (DSMB) review of the one-month safety data for all the
      Phase 1a subjects. All patients must have documented PAH diagnosed within the last 5 years
      and all need to be on stable background PAH specific agents for at least 4 months.

      The 4 different etiologies of Pulmonary Arterial Hypertension (PAH) included in this (IND)
      (IPAH, HPAH, PAH-CTD, PAH-HIV) will be diagnosed based on the following:

      i) clinical features and tests to support a diagnosis of PAH: the diagnosis of PAH requires
      right heart catheterization (RHC) to confirm a hemodynamic profile compatible with PAH. This
      includes a mean pulmonary artery pressure (PAP) ≥ than 25 mmHg at rest, with a pulmonary
      capillary wedge pressure < 15 mmHg. (If slightly elevated, will confirm with LVEDP measure as
      is our usual standard of care) and pulmonary vascular resistance (PVR) of > 3 Wood units. In
      addition, there should be no features to suggest other associations for PAH (also included in
      Group 1) or evidence to suggest PAH owing to left heart disease (Group 2), PH due to lung
      diseases (Group 3), Chronic thromboembolic pulmonary hypertension (Group 4) or miscellaneous
      disorders of unclear mechanism ii) clinical features and tests to support a specific
      designation of each subset of PAH:

        -  Idiopathic PAH (IPAH): This is a diagnosis of exclusion in which a firm diagnosis of PAH
           is made and there are no other etiologies or associations determined that fall into
           Group 1

        -  Heritable PAH (HPAH): This diagnosis is based on a family history of PAH with or without
           a documented genetic mutation associated with PAH (such as BMPR2 mutations that are
           present in up to 75% of HPAH patients). No other PAH association is present.

        -  PAH - Connective Tissue Disease (PAH-CTD): These patients have a confirmed diagnosis of
           PAH as well as firm evidence to support a diagnosis of a connective tissue disease. In
           the REVEAL registry, scleroderma-associated PAH accounted for 60% of PAH-CTD . All
           PAH-CTD cases will be referred by or evaluated by a rheumatologist to ensure a firm
           diagnosis. While all CTDs can be complicated by PAH, the most common associations are
           described below.

             1. Scleroderma (SSc): We use the ACR/EULAR criteria for the diagnosis and
                classification of systemic sclerosis. Patients with SSc-APAH may exhibit features
                of limited scleroderma, such as, calcinosis, Reynaud's, esophageal dysmotility,
                sclerodactyly (with skin thickening of the fingers of both hands extending proximal
                to the metacarpophalangeal joints) and telangiectasia. In those with limited
                scleroderma anticentromere antibodies are commonly positive. In patients with
                diffuse cutaneous scleroderma, SSc-PAH can also be seen. They exhibit diffuse skin
                thickening and tightening. Anti-topoisomerase antibodies (anti Scl70) may be
                positive but interestingly, their absence is more likely to be associated with PAH.
                Other autoantibodies that are associated with an increased risk of SSc-PAH include
                anti-U1-ribonucleoprotein antibodies (RNP), nucleolar pattern of anti-nuclear
                antibody (nucleolar-ANA), and rarely antiphospholipid antibodies.

             2. Systemic Lupus Erythematosus (SLE): We use the Systemic Lupus International
                Collaborating Clinics (SLICC) classification, which requires at least 4/17 criteria
                including at least 1 clinical criterion and 1 immunologic criterion or biopsy
                proven lupus nephritis. On history and physical exam, the following are highly
                suggestive: Photosensitive skin lesions (malar rash or discoid lesions), painless
                ulcers (oral or nasal), features of a serositis, alopecia, Raynaud's,
                arthralgia/arthritis (often migratory) etc. Immunologic antibody studies included
                in SLICC are: Positive ANA, anti-dsDNA, anti-Sm, antiphospholipid, low complement,
                positive direct Coombs test.

             3. Mixed Connective Tissue Disease (MCTD): This is characterized by overlapping
                features of SLE, SSc and polymyositis (PM), as well as high titers of anti-U1
                ribonucleoprotein (RNP). The old term for this is anti-extractable nuclear protein
                (anti-ENA).

             4. Rheumatoid Arthritis (RA): RA is a symmetrical distal inflammatory poly arthritis
                condition. The criteria developed and validated by the American College of
                Rheumatology (ACR) has been used in numerous drug studies which requires at least
                four of these seven criteria for diagnosis (morning stiffness, arthritis of three
                or more joint areas, arthritis of the hands, symmetric arthritis, rheumatoid
                nodules and classic radiographic erosive changes). Immunologic studies include
                positive rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP)
                antibody.

        -  PAH- Human Immunodeficiency Virus (HIV): Patients will have a firm diagnosis with
           positive HIV testing (i.e. positive 4th generation immunoassay and positive confirmatory
           testing such as Western Blot or HIV-1/HIV-2 antibody differentiation immunoassay) and
           managed by an infectious disease/HIV specialist. These patients have hemodynamic
           criteria for PAH present, but the only association on workup is the presence of HIV.
    

Intervention name(s): Allogeneic Human Cardiosphere-Derived Stem Cells; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): Human Allogeneic Cardiosphere-Derived Cells is a biologic product consisting largely of cells grown from donated human heart muscle tissue; For use in Phase 1b - Double-blind randomized control portion of the study
Other intervention name(s): CAP-1002
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The study is divided into two portions. The first (Phase 1a) evaluates safety and efficacy of 2 different doses of cells (50 and 100 million cells). The second phase (Phase 1b) takes place after an independent data safety monitoring board has reviewed all the data from Phase 1a and deems it safe and appropriate to proceed to Phase 1b. The latter is a randomized double-blind study in which subjects receive either CAP-1002 or placebo in a 1:1 ratio.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: HPAH (heritable); IPAH (idiopathic); PAH-CTD (connective tissue diseases); PAH-HIV (human immunodeficiency virus)