NR in Chemo-induced Peripheral Neuropathy

NCT03642990 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 201612723R21CA208968
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this single-arm phase II trial is to determine whether nicotinamide riboside (NIAGEN®) prevents the progression of peripheral sensory neuropathy in patients receiving infusions of paclitaxel or nab-paclitaxel for the treatment of metastatic breast cancer or recurrent platinum-resistant ovarian, endometrial, peritoneal, fallopian tube cancer or metastatic head and neck cancer.

Conditions

Chemotherapy-induced Peripheral Neuropathy; Breast Cancer Metastatic; Platinum-resistant Recurrent Ovarian Cancer; Head and Neck Cancer Stage IV; Endometrial Cancer Stage IV

Keywords

paclitaxel; nicotinamide riboside; NIAGEN; nab-paclitaxel

Outcome Measures

Primary Outcomes (1)

• Number of Participants With No Worsening in the Grade of Peripheral Sensory Neuropathy as Scored by CTCAE

  The primary outcome variable is defined as no worsening of the grade of peripheral sensory neuropathy as scored according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 guidelines. Per the CTCAE a score of 1 would be assigned in the instance of parethesias or a loss of deep tendon reflexes. A score of 2 would be assigned in the instance of moderate symptoms that limit instrumental activities of daily living. A score of 3 would be assigned in the instance of severe symptoms that limit self-care activities of daily living. Because the outcome measure is defined as no worsening of the grade, it was recorded as either "yes"( i.e. it worsened) or "no" (i.e. it did not worsen).

  approximately 4 weeks

Secondary Outcomes (4)

• Percentage of Patients in Which Dose of Paclitaxel or Nab-Paclitaxel is Reduced Due to CIPN

  3 weeks

• Number of Dose Reduction Events

  3 weeks

• Total Dose of Paclitaxel Administered

  3 weeks

• Difference in Score Between Baseline and End of Treatment for the FACT&GOG-NTX Subscale .

  4 weeks

Other Outcomes (1)

• Difference in Total Neuropathy Score Between Screening and End of Treatment

  4 weeks

Study Arms (1)

NIAGEN®)

EXPERIMENTAL

Daily oral administration of nicotinamide riboside 300 mg (150 mg a.m. and p.m.) for one week with dose escalation to 1000 mg (500 mg a.m. and p.m.) for remaining 11 weeks.

Drug: Nicotinamide Riboside

Interventions

Nicotinamide Riboside DRUG

Capsule

Also known as: NIAGEN®)

NIAGEN®)

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be able to give written informed consent and HIPAA authorization
• Be 18 to 85 years old
• Have been diagnosed with stage IV breast cancer of any type, platinum-resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or platinum-resistant recurrent or metastatic head and neck cancer and are anticipated to survive for at least three months
• Have an ECOG Performance Status of 0-2
• Able to take medication orally - up to four capsules in the morning (am) and four capsules in the evening (pm).
• Be undergoing infusions of paclitaxel or nab-paclitaxel for treatment of breast cancer, platinum-resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or platinum-resistant recurrent or metastatic head and neck cancer and be determined to have at least a grade 1 neuropathy based on the CTCAE version 4.03 guidelines for peripheral sensory neuropathy. Breast cancer patients may also be treated concomitantly with monoclonal antibodies to HER2 such as trastuzumab (Herceptin) and pertuzumab (Perjeta). Patients with platinum-resistant ovarian, peritoneal, endometrial, or fallopian tube cancer or platinum-resistant recurrent or metastatic head and neck cancer may also be treated concomitantly with a vascular endothelial growth receptor 2 inhibitor such as bevacizumab (Avastin) or a checkpoint inhibitor.
• Females must be either postmenopausal for at least 1 year or surgically sterile for at least 6 weeks. Females of childbearing potential must have a negative pregnancy test at screening to be eligible for study participation, and agree to take appropriate precautions to avoid pregnancy from screening through follow-up.
• Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up. The following methods have been determined to be more than 99% effective (\<1% failure rate per year when used consistently and correctly) and are permitted under this protocol for use by the patient and his/her partner:
• Complete abstinence from sexual intercourse when this is in line with the preferred and usual lifestyle of the patient
• Double barrier methods including condom with spermicide in conjunction with use of an intrauterine device or condom with spermicide in conjunction with use of a diaphragm
• Surgical sterilization (bilateral oopherectomy with or without hysterectomy, tubal ligation or vasectomy) at least 6 weeks prior to taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol.
• Non-hormonal intrauterine device used as directed by provider placing this is also acceptable.

You may not qualify if:

• Pre-existent peripheral neuropathy that is unrelated to chemotherapy
• Pre-existent chemotherapy-induced peripheral neuropathy greater than grade 2
• Known metastases to the brain, spinal cord or peripheral nerves, or leptomeningeal disease
• Concurrent administration of a poly (ADP-Ribose) polymerase inhibitor (e.g. olaparib, rucaparib)
• Concurrent administration of a platinum-based chemotherapy
• Diabetes requiring management by medication
• Diabetes managed by medication
• Neutrophils \< 1,000 cells/m3
• Hemoglobin \< 8.0 g/dcl
• Platelets \< 100,000 cells/m3
• Creatinine clearance \< 30 ml/min
• AST or ALT values \> 2.5 X upper limits of normal
• Total bilirubin \> 2.0 X upper limits of normal
• Heavy alcohol use defined at \> 8 drinks/week by women or 12 drinks/week by men
• Chronic pain greater than 3 months duration within the past year.

Sponsors & Collaborators

• Donna Hammond, PhD: lead
• National Cancer Institute (NCI): collaborator
• ChromaDex, Inc.: collaborator

Study Sites (2)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Wake Forest Baptist Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157, United States

Location

Related Publications (23)

• Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec;155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23.

  PMID: 25261162 BACKGROUND

• Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol. 2012 Apr;82(1):51-77. doi: 10.1016/j.critrevonc.2011.04.012. Epub 2011 Sep 10.

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• Argyriou AA, Kyritsis AP, Makatsoris T, Kalofonos HP. Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature. Cancer Manag Res. 2014 Mar 19;6:135-47. doi: 10.2147/CMAR.S44261. eCollection 2014.

  PMID: 24672257 BACKGROUND

• Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: A comprehensive survey. Cancer Treat Rev. 2014 Aug;40(7):872-82. doi: 10.1016/j.ctrv.2014.04.004. Epub 2014 Apr 18.

  PMID: 24830939 BACKGROUND

• Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 2013 Nov-Dec;63(6):419-37. doi: 10.3322/caac.21204.

  PMID: 24590861 BACKGROUND

• Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004 May 14;117(4):495-502. doi: 10.1016/s0092-8674(04)00416-7.

  PMID: 15137942 BACKGROUND

• Trammell SA, Yu L, Redpath P, Migaud ME, Brenner C. Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk. J Nutr. 2016 May;146(5):957-63. doi: 10.3945/jn.116.230078. Epub 2016 Apr 6.

  PMID: 27052539 BACKGROUND

• Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):657-61. doi: 10.1097/MCO.0b013e32836510c0.

  PMID: 24071780 BACKGROUND

• Hamity MV, White SR, Walder RY, Schmidt MS, Brenner C, Hammond DL. Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats. Pain. 2017 May;158(5):962-972. doi: 10.1097/j.pain.0000000000000862.

  PMID: 28346814 BACKGROUND

• Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933. doi: 10.1038/srep26933.

  PMID: 27230286 BACKGROUND

• Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 2008;5(2):93-106. doi: 10.1177/1740774508089279.

  PMID: 18375647 BACKGROUND

• Yang Y, Sauve AA. NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016 Dec;1864(12):1787-1800. doi: 10.1016/j.bbapap.2016.06.014. Epub 2016 Jun 29.

  PMID: 27374990 BACKGROUND

• Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305(5686):1010-3. doi: 10.1126/science.1098014.

  PMID: 15310905 BACKGROUND

• Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006 Aug 16;26(33):8484-91. doi: 10.1523/JNEUROSCI.2320-06.2006.

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• Sasaki Y, Vohra BP, Lund FE, Milbrandt J. Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J Neurosci. 2009 Apr 29;29(17):5525-35. doi: 10.1523/JNEUROSCI.5469-08.2009.

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• Sasaki Y, Vohra BP, Baloh RH, Milbrandt J. Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo. J Neurosci. 2009 May 20;29(20):6526-34. doi: 10.1523/JNEUROSCI.1429-09.2009.

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• Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr 23.

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• Khan NA, Auranen M, Paetau I, Pirinen E, Euro L, Forsstrom S, Pasila L, Velagapudi V, Carroll CJ, Auwerx J, Suomalainen A. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med. 2014 Jun;6(6):721-31. doi: 10.1002/emmm.201403943.

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• Conforti L, Gilley J, Coleman MP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci. 2014 Jun;15(6):394-409. doi: 10.1038/nrn3680.

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• Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown R, Janeckova L, Vargas ME, Worrell LA, Loreto A, Tickle J, Patrick J, Webster JR, Marangoni M, Carpi FM, Pucciarelli S, Rossi F, Meng W, Sagasti A, Ribchester RR, Magni G, Coleman MP, Conforti L. A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ. 2015 May;22(5):731-42. doi: 10.1038/cdd.2014.164. Epub 2014 Oct 17.

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• Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7.

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• Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017.

  PMID: 29211728 BACKGROUND

• Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47. doi: 10.1016/j.cmet.2012.04.022.

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MeSH Terms

Conditions

Head and Neck Neoplasms; Endometrial Neoplasms

Interventions

nicotinamide-beta-riboside

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Limitations and Caveats

This trial was limited to a non-curative population of women receiving taxane chemotherapy without added platinum-based agents. Difficulty in recruiting this small population led to eventual termination of the trial. Dose escalation to 1000 mg/day did not occur for any subject due to physician concerns that subjects were not tolerating the 300 mg dose well.

Results Point of Contact

• Title: Donna L. Hammond, Ph.D Professor
• Organization: University of Iowa

donna-hammond@uiowa.edu

319-335-9595

Study Officials

• Donna L Hammond, PhD

  University of Iowa

  PRINCIPAL INVESTIGATOR

• Alexandra Thomas, MD

  Wake Forest Baptist Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: All subjects with stage IV breast cancer, platinum-resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or platinum-resistant recurrent or metastatic head and neck cancer will receive 300 mg NIAGEN®) daily for one week followed by dose escalation to 1000 mg daily for 11 weeks upon reporting the development of grade 1 sensory neuropathy. Those presenting with a residual sensory neuropathy of ≤ 2 as a result of prior chemotherapy will also be enrolled.

Study Record Dates

• First Submitted: August 20, 2018
• First Posted: August 22, 2018
• Study Start: November 8, 2019
• Primary Completion: August 18, 2021
• Study Completion: February 24, 2022
• Last Updated: April 12, 2023
• Results First Posted: April 12, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be available for sharing immediately after publication and ending 5 years after article publication.
• Access Criteria: IPD will be accessible to researchers who provide a methodologically sound proposal, to achieve aims in the approved proposal.

Locations

US (2)