Emgality® (Galcanezumab)

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Galcanezumab: Use of Concomitant Medications in Phase 3 Studies

Certain concomitant medications were allowed in clinical trials, including some with specific restrictions. The majority of patients recorded concomitant medication usage during the studies, the most frequently used are summarized below.

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Description of Analysis

This medical response may not completely match the information in the current local labeling for GALCANEZUMAB. Please see local labeling for approved label information.

Galcanezumab has been studied in phase 3, randomized, double-blind, placebo-controlled studies in adult patients for the prevention of

  • episodic migraine (EVOLVE-1 and EVOLVE-2)1,2
  • chronic migraine (REGAIN),3 and
  • episodic or chronic migraine that has not benefited from 2 to 4 previous migraine prevention medication categories (CONQUER).4

Concomitant Medications in Phase 3, Randomized, Double-Blind, Placebo-Controlled Studies for Migraine Prevention

As shown in Appendix Treatments Allowed and Treatments Not Allowed as Concomitant Therapy During the Treatment Phase in Galcanezumab Phase 3, Double-Blind, Placebo-Controlled Migraine Prevention Studies, medications or classes of medications, herbal remedies, and physical treatments (such as electrical stimulation or physical therapy on the head or neck area) with potential for impact on migraine headache outcome were disallowed.5 Otherwise, concomitant medications without potential impact on migraine were permitted although some required stabilization prior to study entry in order to decrease potential confounding factors. Patients with prior exposure to therapeutic antibodies were excluded.5

Medications Allowed for the Acute Treatment of Migraine Headaches or Other Pain or Injury

Medications allowed for the acute treatment of migraine headaches or other pain or injury during phase 3 migraine prevention studies included1-5

  • acetaminophen (paracetamol)
  • NSAIDs
  • triptans
  • ergotamine and derivatives
  • isometheptene mucate
  • dichloralphenazone and acetaminophen combination (Midrin), or
  • combinations thereof.1,4,5

Medications allowed with restrictions included

  • opioid and barbiturates no more than 3 days/month in the EVOLVE-1, EVOLVE-2, and REGAIN studies
  • opioid and barbiturates no more than 4 days/month in the CONQUER study, and
  • single dose of injectable steroids only once during the study in an emergency setting.1-5

Medications Allowed for Migraine Prevention

In general, migraine preventive treatments were not allowed at any time in the EVOLVE-1, EVOLVE-2, and CONQUER studies from the start of the prospective lead-in phase through the end of the double-blind treatment period.1,2,4,5

However, in the chronic migraine prevention study (REGAIN), up to 1/3 of enrolled patients were allowed to continue migraine prophylactic treatment with either topiramate or propranolol if

  • the patient had been on a stable dose for at least 2 months prior to baseline, and
  • dosing remained stable throughout the double-blind treatment period.3,5

Patients discontinued botulinum toxin A or B in the head or neck area at least

  • 4 months prior to baseline in the EVOLVE studies and REGAIN,1-3,5 and
  • 3 months prior to baseline in the CONQUER study.4

Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Treatment

The most frequently used concomitant medications during double-blind treatment recorded by patients are listed in Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Treatment in Migraine Prevention Trials.5 Across the migraine prevention studies, 79.6% to 92.8% used a concomitant therapy during the study. In the open-label treatment phase of the REGAIN study, 87.4% of patients used a concomitant therapy. There were statistically significant differences between treatment groups in the use of some concomitant medications; however, none of the differences were believed to be clinically meaningful or have an impact on study outcomes.

Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Treatment in Migraine Prevention Trials5

Concomitant Medicationa

EVOLVE-1 (N=858)

EVOLVE-2 (N=915)

REGAIN (N=1113)

CONQUER (N=462)

Ibuprofen

35.6%

30.2%

23.6%

6.9%

Paracetamol (acetaminophen)

21.8%

19.6%

16.1%

9.1%

Thomapyrin N

19.9%

10.6%

8.5%

NA

Sumatriptan

14.7%

12.2%

12.0%

NA

Vitamins not otherwise specified

13.3%

5.8%

6.1%

NA

Naproxen

8.2%

5.7%

6.6%

NA

Vitamin D not otherwise specified

8.2%

N/A

NA

NA

Naproxen sodium

7.9%

5.7%

5.8%

NA

Cetirizine hydrochloride

7.1%

6.9%

NA

NA

Salbutamol (albuterol)

5.8%

NA

NA

NA

Diphenhydramine hydrochloride

5.8%

NA

NA

NA

Loratadine

5.2%

NA

NA

NA

Acetylsalicylic acid

NA

6.9%

5.7%

NA

Ketorolac

NA

5.7%

NA

NA

Levothyroxine sodium/levothyroxine

NA

5.8%

NA

9.5%

Topiramate

NA

NA

10.3%

NA

Omeprazole

NA

NA

5.8%

6.7%

Levonorgestrel

NA

NA

NA

5.2%

Abbreviations: eCRF = electronic case report form; ePRO = electronic patient-reported outcomes; NA = not applicable.

aIn the EVOLVE-1, EVOLVE-2, and REGAIN studies, concomitant medication use was recorded using the ePRO diary. In the CONQUER study, concomitant medication use was recorded using a general concomitant medication eCRF.

Concomitant Medications in Phase 3 Cluster Headache Clinical Trials

Galcanezumab was studied in 2 phase 3, randomized, double-blind, placebo-controlled studies in adults with

  • episodic cluster headache (CGAL), and
  • chronic cluster headache (CGAM).6,7

The studies had a double-blind treatment duration of

  • 2 months for episodic cluster headache, and
  • 3 months for chronic cluster headache, with an optional 12-month open-label extension phase.6,7

Concomitant medication use was allowed per study protocols.5

Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Phases of Cluster Headache Trials

The most frequently used concomitant medications during double-blind treatment recorded using the eCRF are listed in Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Phases of Cluster Headache Trials. Across the 2 cluster headache trials, 67% to 92% of patients used a concomitant therapy during the study. There were statistically significant differences between treatment groups in the use of some concomitant medications; however, none of the differences were believed to be clinically meaningful or have an impact on study outcomes.5

Most Frequently Used Concomitant Medications (≥5%) During Double-Blind Phases of Cluster Headache Trials5

Concomitant Medication

CGAL (N=106)

CGAM (N=237)

Sumatriptan

19.8%

19.8%

Acetylsalicylic acid

8.5%

4.2%

Paracetamol (acetaminophen)

7.6%

11.4%

Levothyroxine sodium

7.6%

7.2%

Verapamil

6.6%a

50.2%

Ibuprofen

6.6%

5.5%

Oxygen

5.7%

8.0%

Zolmitriptan

5.7%

3.8%

Omeprazole

3.8%

5.9%

Topiramate

1.9%

9.3%

Lithium

NA

13.1%

Valproate

NA

6.3%

Abbreviation: NA = not applicable.

aThere were 7 patients who took verapamil, an excluded medication in CGAL, with the majority in the placebo group (n=6 [10.5%] vs. n=1 [2.0%] galcanezumab). All 7 patients discontinued the treatment phase due to lack of efficacy, thus required use of a medication intended to reduce the frequency of cluster headache attacks

Medications Allowed for Acute Treatments of Cluster Headache Attacks

During double-blind treatment, patients were allowed to use the following acute treatments for their cluster headache attacks including

  • high-flow oxygen
  • oral triptans
  • sumatriptan subcutaneous injections
  • sumatriptan nasal spray
  • zolmitriptan nasal spray
  • paracetamol (acetaminophen), or
  • NSAIDs (except indomethacin).5-7

Medications Intended to Reduce the Frequency of Cluster Headache Attacks

In the episodic cluster headache clinical trial, concomitant interventions for the reduction in frequency of cluster headache attacks were not permitted from the onset of the cluster period (prospective baseline reporting period) through the double-blind treatment period.5,6 Interventions for reduction in frequency of cluster headache attacks included medications, treatments, or procedures.5

During the double-blind treatment phase of the chronic cluster headache study, the allowed concomitant medications intended to reduce the frequency of cluster headache attacks included

  • verapamil (limited to <480 mg/day)
  • lithium
  • valproate
  • gabapentin
  • topiramate, and
  • melatonin.7

Patients remaining on these medications for reduction in frequency of  cluster headache attacks were required to be on a stable dose for at least 2 months prior to the prospective baseline period.7

No other medications, treatments, procedures, or interventions for the reduction in frequency of cluster headache attacks were permitted.7

Other Concomitant Medications and Therapies

Unless otherwise noted, medications or classes of medications, herbal remedies, and physical treatments (such as electrical stimulation) with potential for impact on cluster headache outcome were not allowed. Otherwise, most concomitant medications were permissible, though some required stabilization prior to being allowed in the study in order to avoid confounding.5

References

1Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. http://dx.doi.org/10.1001/jamaneurol.2018.1212

2Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454. http://dx.doi.org/10.1177/0333102418779543

3Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91(24):e2211-e2221. http://dx.doi.org/10.1212/WNL.0000000000006640

4Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-825. http://dx.doi.org/10.1016/S1474-4422(20)30279-9

5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

6Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141. http://dx.doi.org/10.1056/NEJMoa1813440

7Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia. 2020;40(9):935-948. http://dx.doi.org/10.1177/0333102420905321

Glossary

eCRF = electronic case report form

NSAID = nonsteroidal anti-inflammatory drug

Appendix

Concomitant Medications and Therapies Allowed and Not Allowed in the Phase 3 Migraine Prevention Studies

Treatments Allowed and Treatments Not Allowed as Concomitant Therapy During the Treatment Phase in Galcanezumab Phase 3, Double-Blind, Placebo-Controlled Migraine Prevention Studies5

Allowed (Restrictions Noted)

Not Allowed for any Reason or Indication

Acetaminophen (paracetamol)

NSAIDs

Triptans

Ergotamine and derivatives

Isometheptene mucate, dichloralphenazone and acetaminophen combination, or combinations thereofa

Acetazolamide

Acupuncture

Anticonvulsants/Antiepilepticsb

Antipsychotics

Beta-blockersc

Botulinum toxin applied to head/neck area

Cannabis/Cannabinoids

Chiropractic procedures, physiotherapy, TENS or other electric devices on head and neck

Corticosteroids for oral use

Flunarizine

Gabapentind

Herbals with anti-inflammatory effect (feverfew, willow bark, and petasites/butterbur), herbals with sympathomimetic effect (ma-huang, ephedra, bitter orange, and synephrine) and herbals with catecholamine transmitter reuptake inhibition (St. John’s Wort)e

MAOIs

Memantine

Methysergidef

Neurotropin®f

Nerve block in the head/neck areaf

Oxetoronef

Pizotifenf

Pregabalind

Serotonin 5HT2a/2c antagonists, eg, trazodone, nefazodone

Stimulants (prescription strength), eg, methylphenidate, dextroamphetamine, mixed amphetamine salts

Tizanidine

Therapeutic antibodiesgh

TCAs

Triptans for prevention of menstrual-related migraine

Venlafaxine

Verapamil

Opioid and barbituratesi

Single dose of injectable steroidsj

ACE inhibitors
ARBs
Benzodiazepines
Bupropion
Calcium-channel blockers (except verapamil and flunarizine)k
Clonidine
Guanfacine
Mirtazapine
SSRIs/NRIs/SNRIs (other than venlafaxine)
Use of electric devices (ie, TENS), physiotherapy, chiropractic procedures on low back and extremitiesl

 

Beta-blockers, ophthalmic
Cyclandelate
Cyproheptadine
Melatoninm

Abbreviations: ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; CGRP = calcitonin gene-related peptide; 5HT2a/2c = 5-hydroxytryptamine subtype 2a/2c; MAOI = monoamine oxidase inhibitor; NRI = norepinephrine reuptake inhibitor; NSAIDs = nonsteroidal anti-inflammatory drugs; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TENS = transcutaneous electrical nerve stimulation.

aMedications allowed for the acute treatment of migraine headaches or other pain or injury.

bIn the REGAIN study, up to 1/3 of enrolled patients were allowed to continue migraine prophylactic treatment with topiramate if the patient had been on a stable dose for at least 2 months prior to baseline, and dosing remained stable throughout the double-blind treatment period.

cIn the REGAIN study, up to 1/3 of enrolled patients were allowed to continue migraine prophylactic treatment with propranolol if the patient had been on a stable dose for at least 2 months prior to baseline, and dosing remained stable throughout the double-blind treatment period.

dExplicitly disallowed only in the CONQUER study. However, all studies generally disallowed the use of antiepileptic medications for any reason.

eOnly herbals with anti-inflammatory effects were disallowed in the CONQUER study.

fOnly disallowed in the CONQUER study.

gExamples of therapeutic antibodies include adalimumab, infliximab, trastuzumab, and bevacizumab. Patients who are taking, or are expected to take, therapeutic antibodies during the course of the study were excluded from the EVOLVE-1, EVOLVE-2, and REGAIN studies. Patients who have previously completed or were withdrawn from studies investigating galcanezumab or other CGRP antibodies were excluded from all studies.

hPrior use of therapeutic antibodies, other than antibodies to CGRP or its receptor, is allowed if that use was more than 12 months prior to the prospective baseline period in the EVOLVE-1, EVOLVE-2, and REGAIN studies.

iAllowed for the acute treatment of migraine headaches or other pain or injury, no more than 3 days/month from prospective baseline period through double-blind treatment period in the EVOLVE-1, EVOLVE-2, and REGAIN studies; included the open-label extension phase in the REGAIN and CONQUER studies. In the CONQUER study, the restriction was no more than 4 days/month.

jAllowed only once during the study for the acute treatment of migraine headaches or other pain or injury, in an emergency setting from prospective baseline period through double-blind treatment period; included the open-label extension phase in the REGAIN and CONQUER studies.

kThe CONQUER study also disallowed the use of lomerizine.

lRestricted use from the prospective baseline through double-blind treatment periods: use of these medications for indications other than migraine prevention is allowed providing the dose is stable 2 months prior to entering the prospective baseline period and is expected to remain stable from the start of the prospective baseline period through the end of the double-blind treatment period.

mRestricted medication during the prospective baseline and double-blind treatment periods in the EVOLVE-1, EVOLVE-2, and REGAIN studies. Use of these medications for indications other than migraine prevention was allowed.

Fecha de la última revisión: 2020 M11 17


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