Treatment persistence and effectiveness of CGRP monoclonal antibodies versus high evidence conventional oral preventive treatments in adolescents with high-burden migraine: an exploratory retrospective analysis of depersonalized real-world-data from the German Pain e-Registry (GPeR). (PRIME-Teen)

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  AMITRIPTYLINE

  PROPRANOLOL HYDROCHLORIDE

  METOPROLOL

  FLUNARIZINE

  TOPIRAMATE

  VALPROIC ACID

  ERENUMAB

  FREMANEZUMAB

  GALCANEZUMAB

  EPTINEZUMAB
• Anatomical Therapeutic Chemical (ATC) code:
  (N06AA09) amitriptyline

  amitriptyline

  (C07AA05) propranolol

  propranolol

  (C07AB02) metoprolol

  metoprolol

  (N07CA03) flunarizine

  flunarizine

  (N03AX11) topiramate

  topiramate

  (N03AG01) valproic acid

  valproic acid

  (N02CD01) erenumab

  erenumab

  (N02CD03) fremanezumab

  fremanezumab

  (N02CD02) galcanezumab

  galcanezumab

  (N02CD05) eptinezumab

  eptinezumab
• Medical condition to be studied:
  Migraine

Population studied

• Short description of the study population:
  For the present analysis, data of adolescents aged 12-17 years with a physician diagnosis of migraine were identified at the cut-off date of 30 June 2024.
• Age groups:
  • Paediatric Population (< 18 years)

    • Neonate

      • Preterm newborn infants (0 – 27 days)
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)
• Estimated number of subjects:
  422

Study design details

• Study design:
  Retrospective, exploratory analysis of depersonalized routine care data from the GPeR, a web-based, non-interventional registry designed to harmonize and aggregate information on real-world pain care in outpatient practices across Germany.
• Main study objective:
  The primary endpoint was a composite of two clinically central aspects of migraine prevention. First, the treatment episode had to be continued over the entire 6-month observation period without discontinuation due to adverse drug reactions (ADRs) or insufficient efficacy. Second, the patient had to achieve a reduction in monthly migraine days (MMD) of at least 50% from baseline to end of month six. Data on MMDs were derived from patient-reported information on migraine days in the respective observation window. Monthly migraine days with acute medication use (MMDAM) and monthly migraine-related school or work disability days (MMSLD) were assessed in an analogous manner.; Secondary endpoints included absolute and relative changes in MMD, MMDAM and MMSLD from baseline to month six, as well as the distribution of patients across migraine frequency categories [chronic migraine (CM), high-frequency episodic migraine (HFEM), low-frequency episodic migraine (LFEM) and very low-frequency episodic migraine (VLFEM)] at baseline and follow-up. Disability and functional impact were assessed with the Migraine Disability Assessment (MIDAS); migraine-related sleep impairments were evaluated via subitem #6 of the modified Pain Disability Index (mPDI6); health-related quality of life was measured with the physical and mental component scores of the VR-12; analyses of the degree of migraine-related depression, anxiety and stress were performed based on data gathered with the Depression, Anxiety and Stress Scale (DASS-21), and the Marburg Questionnaire on Habitual Health Findings (MQHHF) has been used for the evaluation of the general wellbeing of patients.; For the primary endpoint, the proportion of patients who continued their preventive treatment over the 6-months evaluation period were assessed (component #1 of the PE) and for the MMD (PE component #2) absolute and relative changes were calculated and the proportions of patients with a clinically meaningful improvement vs. baseline (≥50%) were determined.
• Setting:
  Patients served as their own comparators, as we evaluated within-subjects differences with respect to the response due to a) high evidence conventional migraine preventives vs. b) calcitonin-gene-related receptor antagonists (CGRP-mABs)
• Comparators:
  High evidence conventional migraine preventive treatments (with beta-blocking agents, tricyclic antidepressants, flunarizine, topiramate or valproic acid) and CGRP-mABs (erenumab, fremanzumab, galcanezumab, eptinezumab).
• Outcomes:
  Absolute and relative changes in monthly migraine days (MMD), monthly migraine days with acute medication (MMDAM) and monthly migraine sick-leave days (MMSLD) from baseline to month six, as well as the distribution of patients across migraine frequency categories [chronic migraine (CM), high-frequency episodic migraine (HFEM), low-frequency episodic migraine (LFEM) and very low-frequency episodic migraine (VLFEM)] at baseline and follow-up. Disability and functional impact were assessed with the Migraine Disability Assessment (MIDAS); migraine-related sleep impairments were evaluated via subitem #6 of the modified Pain Disability Index (mPDI6); health-related quality of life was measured with the physical and mental component scores of the VR-12; analyses of the degree of migraine-related depression, anxiety and stress were performed based on data gathered with the Depression, Anxiety and Stress Scale (DASS-21), and the Marburg Questionnaire on Habitual Health Findings (MQHHF) has been used for the evaluation of the general wellbeing of patients.
• Data analysis plan:
  Response to both treatment alternatives was evaluated over 6-month periods and absolute/relative changes vs. baseline were assessed. Continuous variables were characterized by mean, standard deviation (SD), median and range. Categorical variables were summarized as absolute and relative (if necessary adjusted) frequencies. Differences in continuous changes between CGRP-mABs episodes and conventional preventive episodes were evaluated using student´s t-test. For dichotomous endpoints, such as achievement of the primary composite endpoint or a distinct improvement in a given measure, chi-square analyses, odds ratios (ORs) and relative risks (RR) – both with 95% confidence intervals (CI) – were calculated. From responder proportions, number-needed-to-treat (NNT) or harm (NNH) values were derived to quantify the clinical benefit/risks of CGRP-mABs compared with HECP. Finally, effect size (ES) measures (e.g. Cohen´s d and phi-coefficient) were used to gain insight into the clinical relevance of biometrical differences found.
• Summary results:
  A total of 422 adolescents contributed data on 1448/422 treatment episodes with HECP/CGRP. Premature discontinuation occurred in 68.8 vs. 11.9% of HECP vs. CGRP episodes (p<0.001; OR/RR: 0.06/0.17, ES: 0.571; NNH: 2). Corresponding 6-months treatment persistence was 30.6/88.2% (p<0.001). MMD improved with HECP/CGRP from 11.7/11.6 at BL (p=0.673) to 9.4/4.4 (p<0.001; ES: 0.715). A ≥50% reduction in MMD occurred with HECP/CGRP in 25.4/70.9% (p<0.001; ES: 0.455; NNT: 2), and the PE was reached by 23.7/69.9% (OR/RR: 7.5/3.0; p<0.001; ES: 0.223; NNT: 2). Highest response rates were seen for the CGRP-mAB fremanezumab (75.5%), lowest for the HECP amitriptyline (20.5%; OR/RR: 11.9/3.7; p<0.001). Compared to HECP, CGRPs were followed by significantly larger improvements of MMDAM (60.6 vs. 20.6%; <0.001; ES: 1.196), MMSLD (67.3 vs. 20.5%; p<0.001; ES: 1.408), and MIDAS scores (59.1 vs. 18.9%; p<0.001; ES: 1.294). Psychological, sleep, general wellbeing and quality-of-life outcomes improved in 75.8-93.6% of CGRP episodes, compared with 26.1-31.1% under conventional therapy.