01 March 2017 by Hap Farber

A phase 2 placebo-controlled, randomized, double-blind clinical study to assess the efficacy, safety and tolerability of two doses of pulsed, inhaled nitric oxide (iNO) in patients with WHO Group 1 pulmonary arterial hypertension (PAH): 12 month interim analysis of open label extension

Rationale

iNO is a selective pulmonary vasodilator. Clinical experience suggests iNO has potential to treat PAH.

Methods

A Phase 2 placebo-controlled trial of two dose of iNO in PAH patients who required at least one background PAH therapy was completed. After 16 weeks of blinded treatment (Part 1, n=80), patients entered the long-term extension phase (Part 2). In Part 2 the patients originally receiving iNO 75 mcg/kg (IBW/hr) or iNO 25 mcg/kg (IBW/hr) remained on their assigned treatment, while patients from the placebo group were randomized (double-blind) to either iNO 75 or 25 mcg/kg. Eleven patients randomized to iNO and 4 patients randomized to placebo in Part 1 did not enter Part 2. In Part 2, the primary endpoint was pulmonary vascular resistance (PVR), and a key secondary endpoint was six minute walk distance (6 MWD), both assessed as the change from the time of randomization to 25 mcg/kg or 75 mcg/kg iNO to 12 months. The primary analysis included all patients randomly assigned to 25 or 75 mcg/kg iNO (N=76), while exploratory analyses included an assessment by subgroups on (LTOT) and not on (non LTOT) long-term oxygen therapy.

Results

During the 12 month interval from randomization to 25 mcg/kg or 75 mcg/kg iNO, 28 of 76 patients discontinued iNO without evaluation of PVR and 3 patients died. Twelve months after randomization, 6 of 37 (16%) patients who received iNO 25 mcg/kg and 9 of 39 (23%) patients who received iNO 75 mcg/kg had ≥ 20% reduction in PVR (Table 1), while 6 of 37 (16%) patients who received iNO 25 mcg/kg and 10 of 39 (26%) patients who received iNO 75 mcg/kg had ≥ 50 meter increase in 6MWD (Table 2).  The tables suggest efficacy may differ according to LTOT status.

In patients with ≤ 32 months of exposure, serious adverse events (SAE) occurred in 5/32 in the 25 mcg/kg group and 12/33 in the 75 mcg/kg groups. Unexpectedly, drug-related SAEs occurred in 6 and 0 patients, respectively. 

Conclusion

In this small Phase II trial without a long term control regimen, even though caution is needed when considering signals of efficacyespecially inexploratory subgroup analyses, the data suggest interest in further evaluation of the 75 mcg/kg group, potentially focusing on subjects on LTOT where adherence may be enhanced. The sponsor plans a phase III trial

Key Contributors

R. Benza1, R. Barst2, J. Granton3, D. Badesch4, A. Frost5, H. Farber6, N. Hirani7, W. Hill8, S. Shapiro9, D. Quinn10, T. Fleming 11, G. Elliott12 Affiliations: 1Allegheny General Hospital, Pittsburgh, PA, USA, 2Columbia University College of Physicians and Surgeons, New York, NY (deceased), 3University of Toronto, Toronto, Ontario, Canada, 4University of Colorado Hospital, Denver, CO, USA, 5Baylor college of Medicine, Houston, TX, USA, 6Boston University School of Medicine, Boston, MA, USA, 7University of Calgary, Calgary, Alberta, Canada, 8West Los Angeles VA Healthcare Center, Los Angeles, CA, USA, 9David Geffen UCLA School of Medicine, Los Angeles, CA, USA, 10Bellerophon Therapeutics, Warren, NJ, USA, 11 University of Washington, Seattle, WA, USA,12Intermountain Medical Center, Murray, UT, USA


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