Effects of naltrexone exposure observed in two phase three studies with ALO-02, an extended-release oxycodone surrounding sequestered naltrexone

Joseph S. Gimbel, MD; Richard L. Rauck, MD; Almasa Bass, PharmD; Jacquelyn Wilson, PharmD; Glenn Pixton, MS; Bimal Malhotra, PhD; Gary Wilson PhD; Gernot Wolfram, MD

doi:10.5055/jom.2019.0530

Authors

Joseph S. Gimbel, MD
Richard L. Rauck, MD
Almasa Bass, PharmD
Jacquelyn Wilson, PharmD
Glenn Pixton, MS
Bimal Malhotra, PhD
Gary Wilson PhD
Gernot Wolfram, MD

DOI:

https://doi.org/10.5055/jom.2019.0530

Keywords:

opioids, oxycodone, substance withdrawal syndrome, opioid overdose, naltrexone

Abstract

Objective: To evaluate the clinical effects of naltrexone following ALO-02 administration.

Design: Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362).

Setting: Seventy US research centers.

Patients: Eight hundred and five patients with moderate-to-severe chronic noncancer pain (n = 395) or moderate-to-severe chronic low back pain (n = 410).

Interventions: Oral ALO-02 capsules (daily dose 20-160 mg oxycodone): openlabel titration followed by double-blind fixed dose ALO-02 or placebo (12 weeks) for the efficacy study; and open-label administration (≤12 months) for the safety study.

Main outcome measures: Brief Pain Inventory-Short Form (BPI-sf), withdrawal-related adverse events, Clinical Opiate Withdrawal Scale (COWS), and naltrexone plasma concentrations.

Results: ALO-02 was received for > 30 days by 592 patients (73.5 percent), > 90 days by 348 patients (43.2 percent), and ≥361 days by 105 patients (13.0 percent). Maximum COWS scores were below the cutoff for mild withdrawal for the majority of patients: 86.6 percent of patients in the safety study, and for the efficacy study, 96.8 percent during titration and 95.0 percent during double-blind treatment. The frequency of quantifiable naltrexone plasma concentrations was similar between studies (18-23 percent of samples), and the levels were low, generally not exceeding 200 pg/mL. There was no apparent relationship between naltrexone plasma concentrations and COWS scores (total or change from baseline), or change from baseline in BPI-sf scores in the efficacy (R 2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R 2 = 0.0010, 0.0000, and 0.0122, respectively).

Conclusions: Naltrexone plasma concentrations were low, not correlated with COWS or BPI-sf scores, and considered clinically insignificant.

Author Biographies

Joseph S. Gimbel, MD

Arizona Research Center, Phoenix, Arizona

Richard L. Rauck, MD

Center for Clinical Research, Carolinas Pain Institute, Winston-Salem, North Carolina

Almasa Bass, PharmD

Pfizer Inc, Durham, North Carolina

Jacquelyn Wilson, PharmD

Pfizer Inc, Sanford, North Carolina

Glenn Pixton, MS

Pfizer Inc, Durham, North Carolina

Bimal Malhotra, PhD

Pfizer Inc, New York City, New York

Gary Wilson PhD

Pfizer Inc, New York City, New York

Gernot Wolfram, MD

Pfizer Inc, Durham, North Carolina

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