can recombinant zoster vaccine administration decrease ......lal et al. n engl j med...
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Can Recombinant Zoster Vaccine Administration Decrease the Use of Herpes Zoster-Related Pain Medication across
Randomized Controlled Studies?
Joon Hyung Kim,1 Robert Johnson,2 Martina Kovac,1a Anthony L. Cunningham,3,4 Srikanth Emmadi,5 Keith Sullivan,6 Alemnew F. Dagnew,1b
Desmond Curran,5 Anne Schuind1c
1GSK, Rockville, MD, United States; 2University of Bristol, Faculty of Health Sciences, Bristol, United Kingdom; 3The Westmead Institute for Medical Research, Westmead, NSW, Australia; 4University of Sydney,
Sydney, NSW, Australia; 5GSK, Wavre, Belgium; 6Duke University Medical Center, Durham, NC, United States
Current affiliations: aPPD, Bethesda, MD, United States; bBill & Melinda Gates Medical Research Institute, Cambridge, MA, United States; cPATH, Washington, DC, United States
IDWeek 2020 Virtual meeting, 21–25 October 2020 1
• Joon Hyung Kim, Martina Kovac, Srikanth Emmadi, Alemnew F. Dagnew, Desmond Curranand Anne Schuind were employed by the GSK group of companies at the time the studies were designed, initiated and/or conducted and declare financial and non-financial relationships and activities. MK, AD, and AS are currently employed by PPD, the Bill & Melinda Gates Medical Research Institute, and PATH, respectively. JHK, MK, AD, DC and AS hold/held shares/stock options in GSK as part of their remuneration. Robert Johnson reports personal and consulting fees from GSK both during the conduct of the study and outside the submitted work. Anthony L. Cunningham received honoraria paid to his institution from GSK, Merck Sharp & Dohme (Merck), and BioCSL/Sequirus outside the submitted work. Keith Sullivan receives consulting fees from Magenta, Kiadis, GSK, Talaris, and Xenikos outside the submitted work.
• Funding: GlaxoSmithKline Biologicals SA
• Medical writing and editorial support were provided by Kristel Vercauteren and Sander Hulsmans(Modis c/o GSK)
Disclosures
Acknowledgments
2
Background
1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.
Herpes zoster (HZ) or shingles
3
Background
1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.
Herpes zoster (HZ) or shingles
Older adults or theimmunocompromised are at
increased risk of HZ infection, severe disease and
complications1,2
RISK
4
Background
1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.
Herpes zoster (HZ) or shingles
Has a major impact on patients’ quality of life3
Older adults or theimmunocompromised are at
increased risk of HZ infection, severe disease and
complications1,2
RISK
5
Background
1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.
Herpes zoster (HZ) or shingles
Has a major impact on patients’ quality of life3
~1 OF 6patients with HZ still
have some pain 2 years afteronset4
Older adults or theimmunocompromised are at
increased risk of HZ infection, severe disease and
complications1,2
RISK
6
Background
1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.
Herpes zoster (HZ) or shingles
~1 OF 6patients with HZ still
have some pain 2 years afteronset4
Opioids and other analgesics may be prescribed for pain relief
but there are concerns about long-term effects and potential
misuse4
Has a major impact on patients’ quality of life3
Older adults or theimmunocompromised are at
increased risk of HZ infection, severe disease and
complications1,2
RISK
7
Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults
RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.
Age
% Efficacy against HZ(95% CI)
HZ cases in RZV group (n)HZ cases in placebo group (n)
50+
ZOE-50(NCT01165177)1
70+
ZOE-70(NCT01165229)2
ZOE-HSCT(NCT01610414)3
8
Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults
RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.
Age
% Efficacy against HZ(95% CI)
HZ cases in RZV group (n)HZ cases in placebo group (n)
50+
ZOE-50(NCT01165177)1
s
%*3.7; 99.0)
≥50 year
97.2(9
9 (7,340)254 (7,413)
70+
ZOE-70(NCT01165229)2
ZOE-HSCT(NCT01610414)3
9
Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults
RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.
Age
% Efficacy against HZ(95% CI)
HZ cases in RZV group (n)HZ cases in placebo group (n)
50+
ZOE-50(NCT01165177)1
s
%*3.7; 99.0)
≥50 year
97.2(9
9 (7,340)254 (7,413)
70+
ZOE-70(NCT01165229)2
≥70 years
89.8%(84.2; 93.7)23 (6,541)
223 (6,622)
ZOE-HSCT(NCT01610414)3
10
Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults
RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.
Age
% Efficacy against HZ(95% CI)
HZ cases in RZV group (n)HZ cases in placebo group (n)
50+
ZOE-50(NCT01165177)1
s
%*3.7; 99.0)
≥50 year
97.2(9
9 (7,340)254 (7,413)
70+
ZOE-70(NCT01165229)2
≥70 years
89.8%(84.2; 93.7)23 (6,541)
223 (6,622)
ZOE-HSCT(NCT01610414)3
≥18 years(transplant population)
68.2%(55.6; 77.5)
49 (870)135 (851)
11
Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults
RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.
Age
% Efficacy against HZ(95% CI)
HZ cases in RZV group (n)HZ cases in placebo group (n)
50+
ZOE-50(NCT01165177)1
s
%*3.7; 99.0)
≥50 year
97.2(9
9 (7,340)254 (7,413)
70+
ZOE-70(NCT01165229)2
≥70 years
89.8%(84.2; 93.7)23 (6,541)
223 (6,622)
ZOE-HSCT(NCT01610414)3
≥18 years(transplant population)
68.2%(55.6; 77.5)
49 (870)135 (851)
12
Aim
Did RZV have an impact in the few people who developed confirmed HZ (“breakthrough cases”) afterRZV vaccination in the ZOE-50, ZOE-70 and ZOE-HSCT studies?
13
Aim
Did RZV have an impact in the few people who developed confirmed HZ (“breakthrough cases”) afterRZV vaccination in the ZOE-50, ZOE-70 and ZOE-HSCT studies?
14
Efficacy of RZV vaccination in breakthrough cases on:
Duration of clinically
significant HZ-related
pain
Secondary endpoint (all studies)
Aim
Did RZV have an impact in the few people who developed confirmed HZ (“breakthrough cases”) afterRZV vaccination in the ZOE-50, ZOE-70 and ZOE-HSCT studies?
15
Efficacy of RZV vaccination in breakthrough cases on:
Duration of clinically
significant HZ-related
pain
Use of HZ-related pain medication
Secondary endpoint (all studies) Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)
Aim
Did RZV have an impact in the few people who developed confirmed HZ (“breakthrough cases”) afterRZV vaccination in the ZOE-50, ZOE-70 and ZOE-HSCT studies?
16
Efficacy of RZV vaccination in breakthrough cases on:
Duration of clinically
significant HZ-related
pain
Use of HZ-related pain medication
Duration of HZ-related
pain medication
use
Secondary endpoint (all studies) Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)
Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)
Clinically significant pain
Methods
17
Zoster Brief Pain Inventory (ZBPI) questionnaire (only confirmed HZ cases were evaluated)
Least pain in the last 24 hoursWorst pain in the last 24 hoursAverage pain in the last 24 hoursPain right now
0
No PainScore: 0
10
Pain as bad as you canimagine
Score: 10 ZBPI questions:
Clinically significant pain
Methods
18
Zoster Brief Pain Inventory (ZBPI) questionnaire (only confirmed HZ cases were evaluated)
Least pain in the last 24 hoursWorst pain in the last 24 hoursAverage pain in the last 24 hoursPain right now
0
No PainScore: 0
10
Pain as bad as you canimagine
Score: 10
103
ZBPI questions:
Clinically significant pain
Methods
19
Zoster Brief Pain Inventory (ZBPI) questionnaire (only confirmed HZ cases were evaluated)
Least pain in the last 24 hoursWorst pain in the last 24 hoursAverage pain in the last 24 hoursPain right now
Medication use for HZ-related pain (only confirmed HZ cases were evaluated)
Manual classification of all HZ-related medications during each episode (post-hoc)
0
No PainScore: 0
10
Pain as bad as you canimagine
Score: 10
103
ZBPI questions:
Results: RZV can reduce the duration of clinically significant HZ-related pain
Vaccine efficacy was assessed by COX proportional hazard model. *This analysis excluded pain linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode and at least 1 day of clinically significant HZ-related pain; tmed, median duration of clinically significant HZ-related pain; T, sum of the duration of clinically significant HZ-related pain (T=1 for participants without pain).
Efficacy in reducing duration of clinically significant pain (95% CI)
9254
7221
11.015.0
1466705
23223
18198
13.519.0
6289633
49135
37120
14.024.0
8926275
N n tmed (days) T (days)
26.9
28.4
38.5
-80% -60% -40% -20% 0% 20% 40% 60% 80%
RZVPlacebo
RZVPlacebo
RZVPlacebo
ZOE-50
ZOE-70
ZOE-HSCT*
20
Results: RZV can reduce HZ-related pain medication use
Efficacy in reducing pain medication use (95% CI)
9254
6190
13529
23223
10160
31631
49135
3294
65262
N n nmed
RZVPlacebo
RZVPlacebo
RZVPlacebo
ZOE-50
ZOE-70
ZOE-HSCT*
11.7
39.6
6.2
-80% -60% -40% -20% 0% 20% 40% 60% 80%
Vaccine efficacy was assessed by asymptotic standardized unconditional binomial test. *This analysis excluded pain medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode who took at least 1 HZ-related pain medication; nmed, number of HZ-related pain medications.
21
Results: RZV can reduce the duration of HZ-related pain medication use
Vaccine efficacy was assessed by COX proportional hazard model. *This analysis excluded pain medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode and at least 1 day of HZ-related pain medication use; tmed, median duration of HZ-related pain medication use; T, sum of theduration of HZ-related pain medication use (T=1 for participants without pain medication).
Efficacy in reducing duration of pain medication use (95% CI)
9254
6190
21.022.0
15914,524
23223
10160
30.038.0
110831,949
49135
3294
21.547.5
191715,465
N n tmed (days) T (days)
RZVPlacebo
RZVPlacebo
RZVPlacebo
ZOE-50
ZOE-70
ZOE-HSCT*
24.7
49.3
22.5
-80% -60% -40% -20% 0% 20% 40% 60% 80%
22
Results: Proportion of participants with confirmed HZ by medicine type in ZOE-50
N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].
ZOE-50
Participants taking at least 1 HZ-related medication
6
3
1
1
3
155
49
21
21
17
55
15
10
24
37
1
54
0% 10% 20% 30% 40% 50% 60% 70%
Non-opioids†
Weak opioids†
Strong opioids†
Corticosteroids
Antidepressants
Psychiatric medications
Anesthetics
Antihistamines
Gastro-intestinal medications
Antibiotics
Muscle relaxants
Other medications
RZV (N=9)
Placebo (N=254)
n
23
Results: Proportion of participants with confirmed HZ by medicine type in ZOE-70
ZOE-70
Participants taking at least 1 HZ-related medication
RZV (N=23)
Placebo (N=223)
6
2
1
1
3
1
2
3
103
30
5
10
18
35
11
9
6
32
2
42
0% 10% 20% 30% 40% 50% 60% 70%
Non-opioids†
Weak opioids†
Strong opioids†
Corticosteroids
Antidepressants
Psychiatric medications
Anesthetics
Antihistamines
Gastro-intestinal medications
Antibiotics
Muscle relaxants
Other medications
N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].
n
24
Results: Proportion of participants with confirmed HZ by medicine type in ZOE-HSCT
ZOE-HSCT
Participants taking at least 1 HZ-related medication
RZV (N=49)
Placebo (N=135)
22
6
5
2
3
8
0
1
2
5
0
6
62
34
12
14
13
42
7
11
2
14
0
19
0% 10% 20% 30% 40% 50% 60% 70%
Non-opioids†
Weak opioids†
Strong opioids†
Corticosteroids
Antidepressants
Psychiatric medications
Anesthetics
Antihistamines
Gastro-intestinaI medications
Antibiotics
Muscle relaxants
Other medications
This analysis excluded medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].
n
25
Conclusions
26
Conclusions
In addition to the high efficacy of RZV in preventing HZ, data from these 3 large clinical efficacy trials indicates that RZV may shorten the duration of HZ-related pain and therefore shorten the duration of pain medication use in breakthrough cases in older adults and HSCT recipients.
27
Conclusions
In addition to the high efficacy of RZV in preventing HZ, data from these 3 large clinical efficacy trials indicates that RZV may shorten the duration of HZ-related pain and therefore shorten the duration of pain medication use in breakthrough cases in older adults and HSCT recipients.
The results from these preplanned secondary and tertiary study endpoints should be interpreted withcaution due to the low number of breakthrough HZ cases (high vaccine efficacy).
28
Conclusions
In addition to the high efficacy of RZV in preventing HZ, data from these 3 large clinical efficacy trials indicates that RZV may shorten the duration of HZ-related pain and therefore shorten the duration of pain medication use in breakthrough cases in older adults and HSCT recipients.
The results from these preplanned secondary and tertiary study endpoints should be interpreted withcaution due to the low number of breakthrough HZ cases (high vaccine efficacy).
By preventing HZ through vaccination, RZV could potentially reduce exposure to opioids and othermedication (see also abstract 902651).
29
Conclusions
In addition to the high efficacy of RZV in preventing HZ, data from these 3 large clinical efficacy trials indicates that RZV may shorten the duration of HZ-related pain and therefore shorten the duration of pain medication use in breakthrough cases in older adults and HSCT recipients.
The results from these preplanned secondary and tertiary study endpoints should be interpreted withcaution due to the low number of breakthrough HZ cases (high vaccine efficacy).
Even in cases when shingles develops in vaccinated people, RZV may reduce its severity and the need for pain relief. These additional benefits of vaccination improve the patient’s quality of life and might mitigate the risk of overmedication.
By preventing HZ through vaccination, RZV could potentially reduce exposure to opioids and othermedication (see also abstract 902651).
30
Thank you
31