Efficacy of two different dosages of prednisolone for treatment of subacute thyroiditis: a single-center, prospective, randomized, open-label, non-inferiority trial

doi:10.21203/rs.3.rs-1756101/v1

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Efficacy of two different dosages of prednisolone for treatment of subacute thyroiditis: a single-center, prospective, randomized, open-label, non-inferiority trial

https://doi.org/10.21203/rs.3.rs-1756101/v1

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Background: The aim of study was to explore the efficacy and safety of low-dose(LD) and regular dose(RD) prednisone (PDN) for treatment of subacute thyroiditis (SAT).

Methods: Patients were randomly allocated using the block randomization method to the two groups. The primary outcome was the time required for PDN treatment. Secondary outcomes included percentages of relapse, mean score for the Morisky Medication Adherence Scale-8©（MMAS-8）, time required for symptoms to resolve, cumulative PDN dose (mg) and mean erythrocyte sedimentation rate (ESR) at 2 weeks and baseline.

Results: The study cohort included 45 patients, randomized 40 participants, and 36 completed the study. There was no significant difference in the treatment duration between the LD and RD groups (48.25±11.42vs.53.30±21.85 days, p=0.379). The mean difference in the time required for PDN treatment between the LD and RD groups was -5.05 (95%CI =-16.61 to 6.51) days, which was within the non-inferiority margin of 7 days. There was a significant difference in the mean score for MMAS-8 between the LD and RD groups (5.94± 0.77vs.5.25±1.12, p=0.037). Also, there was a significant difference in the cumulative PDN dose between the LD and RD groups (447.34±156.74vs.964.75±300.83, p=0.0001).The ESR at 2 weeks was statistically significant as compared to baseline values in both groups, with pre-treatment and post-treatment ESRs of 53.60±26.80 and 18.63±15.00/mm/h, (p<0.0001), in the LD group and 64.20±22.06 and 17.00±8.99/mm/h (p<0.0001) in the RD group.

Conclusions: Low-dose PDN therapy may be sufficient to achieve complete recovery and better outcomes of SAT.

This study is registered with Chinese Clinical Trial Registry (ChiCTR2100051762).

Subacute Thyroiditis

SAT

Low-dose

Prednisone

Non-inferiority

Subacute thyroiditis (SAT), also known as De Quervain's thyroiditis, is the most common type of painful thyroid disorder(1–3). Although the pathogenesis has not been fully elucidated, the incidence of SAT is relatively higher in women and affects individuals aged between 30 to 50 years(2–5). Currently, mild cases of SAT are treated with non-steroidal anti-inflammatory drugs (NSAIDs), while moderate to severe cases, characterized by recurrent neck pain, tenderness, and significant goiter are sometimes treated with short-term steroid therapy. Prednisone (PDN) is a synthetic corticosteroid commonly used for treatment of SAT(4, 6). The 2016 American Thyroid Association (ATA) guideline recommends PDN for treatment of moderate to severe cases of SAT. The recommended steroid regimen includes PDN at 40 mg/day for 1–2 weeks with gradual tapering of the dosage for 2–4 weeks depending on the clinical response. However, in China, SAT is traditionally treated with PDN at 30 mg/day(5), which is also unacceptable to patients. Patients often terminate treatment or reduce the dosage without authorization due to the side effects of high-dose PDN therapy, which can significantly influence the effects of the treatment. Therefore, the aim of this non-inferiority study was to explore the clinical efficacy and safety of low-dose (LD) prednisolone (PDN) at 15 mg one time per day as compared to the regular dose (RD) at 10 mg three times per day for treatment of SAT.

Study Design

We performed a prospective, randomized, open-label, single-center, parallel group controlled, non-inferiority study in the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital) from Dec 1, 2020 to Dec 30, 2021. All patients provided written informed consent and confirmed their willingness to participate.

Participants

Participants diagnosed with SAT were evaluated in terms of eligibility for inclusion in the study. The diagnosis of SAT was based on clinical features, physical examination and laboratory test results, which includes elevated ESR, serum free-thyroxine (fT4), and free triiodothyronine (fT3) levels with a suppressed thyroid-stimulating hormone (TSH) level. The diagnosis and resolution of SAT were confirmed by thyroid ultrasonography in all patients.

In this study, patients with the side effects of steroids and pregnancy were excluded.

Randomization and Blinding

We randomly assigned patients to the 1 of the 2 groups in a 1:1 ratio using random block with stratification (http://www.randomization.com). A study coordinator was only involved in randomization and allocation. Randomized numbers were sealed in opaque envelopes in order and kept concealed until the study day. The investigator made a phone call to the study coordinator the day before patient enrollment to confirm the patient's assignment. Assessment of study outcomes was analyzed by the investigator. The purpose of this study was to explore the efficacy and safety of different doses of PDN for the treatment of SAT, and complete blinding would not be meaningful for either the investigators or the patients. Therefore, this study was conducted as an open-label study in which only laboratory personnel were blinded and no randomization groups were allowed to be removed.

Procedures

The dose tapering protocol is 15-10-5-2.5 and 30-20-15-10-5 mg per week for the LD and RD group, respectively. Treatment duration has been extended by 1 or 2 weeks with the continuation of the same dose in the previous week in patients who complained having an increased pain during the dose tapering. The dose was reduced from the week of normalized ESR (about 7-14 days), and the first reduction was 1/3 of the dose. Based on clinical experience and examination results, most patients experienced complete disappearance of pain within 5-10 days after PDN treatment, either at the small initial dose or at the regular initial dose. Therefore, if patients experienced recurrence of symptoms during the dose reduction, we adjusted them to the regular initial dose.

After the patients were enrolled, we conducted weekly face-to-face or telephone follow-up visits. The results of the follow-up visits were recorded on the patients' informed consent forms. Each participant received a final visit before the completion of the trial.

Outcomes

The primary outcome of the study was assessed the clinical efficacy of different doses of PDN in the treatment of SAT, which was the time (days) required for PDN treatment. The secondary outcomes were: (I)percentages of participants experiencing relapse during and after treatment; (II)the mean score for the Morisky Medication Adherence Scale-8©(MMAS-8); (III)time(days) required for symptoms to resolve;(IV) cumulative PDN dose (mg);(V) the mean erythrocyte sedimentation rate (ESR) at 2 weeks and baseline.

Safety outcomes included the occurrence of all adverse drug events, which was elevated blood pressure, elevated blood glucose, mood swings, facial acne, insomnia, weight gain, hypothyroidism, etc.)

Statistical analysis

Primary and secondary outcomes will be analyzed based on the full-analysis-set, with missing values carried forward using the last observation and a supportive sensitivity analysis using the last follow-up. Safety outcomes will be analyzed based on the safety data set, including the set of all subjects who received at least one treatment after randomization. All outcomes will also be analyzed according to each protocol set. The primary outcome was the time (days) required for PDN treatment. The purpose of this study was to show that low-dose PDN therapy may be sufficient to achieve complete recovery and better outcomes in SAT. Therefore, we hypothesized that the patients randomized to LD group is non-inferior to that of patients randomized to RD group. To assess for non-inferiority, non-inferiority delta of 7（days）was chosen for the following reasons. In previous study(6,7), the mean time was around 36 days with a standard deviation of 12 days. Given the Δ of 7, we calculated the sample size to test the null hypothesis H0: μ1 − μ0 > 7 versus the alternative hypothesis H1: μ1 − μ0 ≤ 7, where, μ1 − μ0 is the mean difference of the time period between the LD group and the RD group (non-inferiority test). Based on 80% power and α = .05 significance level, a total of 40 participants were included in each group, for a total of 80 participants, considering a 5% drop-out rate. However, because of the study was conducted in the midst of a Covid-19 virus pandemic, which prevented some patients from coming to the hospital and the approximate annual number of hospitalized patients with SAT in our department was 40. Finally, only 45 participants were recruited in this study.

All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) v 26.0 software (SPSS, Inc, Chicago, IL). All tests were performed with the a-level set to 0.05 (2-tailed). Data are presented as mean±standard deviation, median (inter-quartile range), or numbers (%) as appropriate. The difference between the randomized groups on baseline variables was assessed using standardized mean difference (SMD). We assessed the effect of LD group vs. RD group on the primary outcome, using a 2-sample t test. Non-inferiority was claimed when the upper limit of the 2-sided 95% confidence interval was below the non-inferiority margin. Time period, the mean score for the MMAS-8, neck pain, tenderness at the region of thyroid gland and cumulative PDN dose(mg) were presented as point estimate and corresponding 95% confidence interval (4). We assessed the treatment effect on normally distributed continuous variables using the 2-sample t test.

Randomized groups were compared on the percentage of relapse during treatment and after treatment using a χ² test or Fisher’s exact test where appropriate, which were also used to assess differences in the incidence of adverse events between treatments. We also used Kaplan-Meier curves and log-rank test to analyze the incidence of recurrent symptoms during treatment and the relapse rate after discontinuation of the drug; P<0.05 was considered a statistically significant difference.

The study design is illustrated in Fig. 1. Of 45 patients who were recruited from Dec 1, 2020 to Dec 30, 2021, five were excluded, including three who did not meet the inclusion criteria and two others who declined to participate in this study. Hence, 40 individuals were enrolled and randomly allocated to the LD group or RD group. All individuals followed the fasting instructions and none developed adverse side effects. No patient quit the study based on the withdrawal criteria. Finally, 36 patients completed the study and the data of 36 patients were included for statistical analysis.

There were no significant differences in the baseline characteristic of the patients assigned to the LD and RD groups (Table 1). The number of patients in the LD and RD groups was 16 and 20, respectively. The LD group consisted of 6 males and 10 females with a median age of 42.50 ± 8.86 (range, 30–71) years, median disease duration before treatment of 15.78 ± 9.45 (range, 3–20) days, and median visual analogue scale (VAS) pain score of 6.63 ± 1.03. The RD group consisted of 6 males and 14 females with a median age of 46.75 ± 12.73 (range, 29–58) years, median disease duration before treatment of 13.54 ± 6.89 (range, 5–15) days, and median VAS pain score of 6.45 ± 1.28. There were no significant differences in sex ratio, age, course, and clinical manifestations between the two groups (p > 0.05).

Table 1

Baseline characteristics
	LD Group (n = 16)	RD Group (n = 20)
Gender
Male	6(37.5%)	6(30%)
Female	10(62.5%)	14(70%)
Age(years)	42.50(8.862)	46.7(12.73)
Laboratory findings
ESR(mm/h)	53.06(26.80)	64.20(22.06)
FT3(pmol/L)	10.39(4.435)	9.90(3.18)
FT4(pmol/L)	40.00(11.54)	31.53(9.35)
TSH(mIU/L)	0.25(0.47)	0.20(0.38)
Symptoms
Fever(℃)	2(12.5%)	3(15%)
Palpitation	0(0%)	1(5%)
Severity score	6.63(1.03)	6.45(1.28)
Duration of symptoms before treatment(days)	15.78(9.45)	13.5(6.89)
Neck pain
Right/Left, n(%)	5(31.25%)	11(55%)
Bilateral, n (%)	11(68.75%)	9(45%)
Data are mean ± SD, median (IQR) or number of patients
ESR = erythrocyte sedimentation rate,
TSH = thyroid-stimulating hormone,
FT3 = free triiodothyronine, FT4 = free thyroxine.

Table 2

Primary endpoint and Secondary endpoint
	LD Group (n = 16)	RD Group (n = 20)	P value	Treatment difference (LD–RD), (95% CI)
Primary endpoint
Time period (days)	48.25 ± 11.42	53.30 ± 21.85	.38^a,b	-5.05(-16.61,6.51)^c
Secondary endpoint
Patients of relapse during treatment	6(37.5%)	9(45%)	.65^d	/
Patients of relapse after stopping treatment	2(12.5%)	1(5%)	.57^d	/
Drug compliance	5.94 ± 0.77	5.25 ± 1.12	.037^b	-0.69(-1.33, -0.05)
Time period of symptom vanishing(days)
neck pain	2.63 ± 0.94	2.42 ± 0.85	.51^b	0.2(-0.81,-0.41)
tenderness at the region of thyroid gland	7.13 ± 1.17	6.48 ± 1.34	.14^b	0.65(-1.52,0.22)
Cumulative PDN dose(mg)	447.34 ± 156.74	964.75 ± 300.82	<0.0001^b	-517.41(-674.47, -358.34)
ESR(mm/h)
baseline	53.06 ± 26.80	64.20 ± 22.06	.18^b	11.138(-5.40,27.68)
2 weeks	18.63 ± 15.00	17.00 ± 8.94	.69^b	-1.625(-9.80,6.55)
Data are presented as mean ± standard deviation, median (inter-quartile range), or number (%).
CI = confidence interval.
^a P value for superiority.
^b Data are compared using student t test.
^c Upper confidence interval limit is less than the noninferiority delta of 7 days, so non-inferiority is claimed.
^d Data are compared using χ2 test.

Table 3

Adverse events in each treatment group
	LD Group (n = 20)	RD Group (n = 20)
Adverse events
All	5(25%)	9(45%)
Gastrointestinal disorders	1(6.2%)	1(5%)
Gain weight	2(12.5%)	3(15%)
Blood glucose increased	0	2(10%)
Hypertension	1(6.2%)	1(5%)
Insomnia	0	1(5%)
Facial acne	0	1(5%)
Hypothyroidism	1(6.2%)	2(10%)
Data are n (%) and are based on the safety analysis set (all patients randomly assigned to treatment groups with documented safety data).

In addition, there was no significant difference in treatment duration between the LD and RD groups (48.25 ± 11.42vs.53.30 ± 21.85 days, respectively, p = 0.379). The mean difference in the time period (days) required for PDN treatment between the LD and RD groups was − 5.05 (95%confidence interval [CI], -16.61 to 6.51) days, which was within the non-inferiority margin of 7 days. There was a significant difference in the mean score for the MMAS-8 between the LD and RD groups (5.94 ± 0.772vs.5.25 ± 1.12, respectively, p = 0.037), but not in the duration of neck pain (2.63 ± 0.94vs. 2.42 ± 0.847 days, respectively, p = 0.051) or tenderness of the thyroid gland (7.13 ± 1.17vs.6.48 ± 1.34 days, respectively, p = 1.137). Also, there was a significant difference in the cumulative PDN dose between the LD and RD groups (447.34 ± 156.74vs. 964.75 ± 300.83, respectively, p = 0.0001). There were also significant differences in the erythrocyte sedimentation rate (ESR) at 2 weeks as compared with baseline in both groups. The pre-treatment and post-treatment ESRs were 53.60 ± 26.80 and 18.63 ± 15.00/mm/h, respectively (p < 0.0001) in the LD group and 64.20 ± 22.06 and 17.00 ± 8.99/mm/h, respectively (p < 0.0001) in the RD group, but there was no significant difference between the two groups before and after treatment. In the LD and RD groups, relapses occurred in 6 (37.5%) and 9 (45%) patients, respectively (p = 0.65). After discontinuation of treatment, there was no significant difference in the incidence of relapses between the LD and RD groups (2[12.5%] vs.1[5%], respectively, p = 0.57).

All adverse events are shown in Table 4. In the LD and RD groups, 5 (25%) and 9 (45%) patients experienced adverse events. The most common adverse event was weight gain followed by gastric discomfort, which occurred at similar rates in the LD and RD groups. However, the total number of patient-reported adverse events was significantly lower in the LD group than the RD group. One patient with type 2 diabetes mellitus in the RD group experienced large fluctuations in blood glucose levels during treatment. One patient in the LD group and two in the RD group developed temporary hypothyroidism.

In this randomized controlled trial, the clinical efficacy and safety of different doses of PDN for treatment of SAT were compared. The results of this study showed that PDN at the LD and RD were effective for treatment of moderate to severe SAT with no significant difference in treatment duration, the incidence of recurrent symptoms during treatment, relapse, or time for clinical symptoms to resolve. However, there were significant differences in compliance, total cumulative PDN dose during treatment, and overall adverse events, which are consistent with previous findings that small doses of hormones are associated with fewer adverse effects and good compliance, thereby mitigating potential organ damage. Overall, the use of smaller doses of PDN was not inferior to conventional doses in terms of total treatment duration.

Although the 2016 ATA guidelines recommend the use of NSAIDs for treatment of mild SAT, the recommended regimen for moderate to severe cases of SAT and patients who do not respond to NSAIDs includes 40 mg of PDN daily for 1–2 weeks and then tapering the dosage for 2–4 weeks depending on the clinical response(4, 8). However, there is relatively little evidence supporting this regimen. The use of high-dose PDN for treatment of SAT is often associated with severe side effects that may be intolerable to some patients, thus several previous studies recommend a starting dose of PDN at 15–60mg(4, 6, 7, 9–13). However, in clinical practice, both small and large doses of PDN have been used to treat SAT cases, depending on the preference of the clinician. According to previous reports(6, 9, 10), the mean duration of the conventional dose of PDN for treatment of SAT is about 36 ± 12 days, although patient compliance was poor and the relapse rate was high. Comparatively, the mean total duration of treatment in this study was 48.25 ± 11.422 days in the LD group and 53.30 ± 21.85 days in the RD group. Hence, the treatment duration of was shorter with low-dose PDN than the conventional dose, which may be related to greater patient compliance, which was superior in the LD group than the RD group, as determined by the MMAS-8, and most patients adhered to the treatment regimen and did not change the dosage arbitrarily. Notably, patient compliance directly influences the effect of drug treatment, which be the reason why treatment duration was significantly shorter in the LD group. Nonetheless, the treatment duration in both the LD and RD groups was greater in the present study than the mean values of previous studies, which may be related to the ethnicity of the patients included in previous studies.

The results of the present study suggest that PDN at both the LD and RD are effective for treatment of SAT. Previous clinical studies have shown that early treatment of SAT with hormones can effectively relieve patient symptoms of thyroid pain and tenderness, improve daily life, and return thyroid function to normal. However, high-dose PDN shock therapy may be an overtreatment because a small dose of PDN is sufficient to achieve recovery, while minimizing the risk of hormone-related complications. In contrast, the use of high doses of hormones often causes severe side effects that could be intolerable to some patients(14–21). Therefore, it is important to control the frequency and dosage of hormone therapy. However, relatively few studies have investigated the efficacy of low-dose PDN for treatment of SAT to minimize the risk of potential side effects associated with high-dose PDN. Hence, in this study, the efficacy of two starting dosages of PDN was compared. The results showed that both regimens were efficacious and achieve the therapeutic goal, although safety and compliance were superior with low-dose PDN and significantly reduced the risk of potential organ damage.

According to previous studies, approximately 5–20% of patients experience relapse of SAT during hormone therapy or after discontinuation(22–24). The results of the present study showed that 6 (37.5%) and 9 (45%) in the LD and RD groups, respectively, experienced recurrent symptoms at the time of drug reduction, while and only 2 (12.5%) patients in the LD group experienced relapse within 1–2 months after discontinuation, as with 1(5%) patient in the RD group within 1 month after discontinuation. However, there was no significant difference in the recurrence rate during treatment or after discontinuation between the groups and all patients were treated in the same manner as the initial episode.

Approximately 30% of patients with SAT experience hypothyroidism and most typically regain normal thyroid function within 1 year(4). The rate of permanent hypothyroidism is previous studies was 5–15%(5, 21), which was similar to the rates of temporary hypothyroidism of 4.8% and 8.7%, respectively, in the LD and RD groups in the present study. Notably, there was no significant difference in the incidence of temporary hypothyroidism between the LD and RD groups, although it was not possible to compare the rates of permanent hypothyroidism. There also exists conflicting data in the literature regarding whether PDN treatment of SAT causes permanent hypothyroidism. Although some previous studies reported higher rates of permanent hypothyroidism with PDN treatment, other studies suggest that hormone therapy may have a protective effect against the development of permanent hypothyroidism(21, 23).

There were several limitations to this study that should be addressed. First, although this study was a prospective randomized controlled trial, the sample size was relatively small, the participants were recruited from a single center, the follow-up time was relatively short, and the study duration was relatively long, which may have biased the results. Therefore, prospective multicenter studies with large sample sizes and longer follow-up times trials are needed to verify these results. Second, the primary outcome of this study was the duration of PDN required to resolve symptoms of SAT. The COVID-19 pandemic prevented some patients from returning to the hospital for follow-up observations at the required time, thus the days of administration and adverse effects of some patients may not have been accurately recorded, which could have biased the study. Due to the relatively short period and the small sample size of this study, some long-term adverse effects, such as permanent hypothyroidism, may have been missed. Therefore, it was difficult to compare the adverse effects between the groups.

In conclusion, the results of this study showed that the efficacy of oral PDN was similar between the LD and RD groups, so LD therapy may be sufficient to achieve complete recovery and better outcomes of SAT.

SAT Subacute thyroiditis

ESR Erythrocyte sedimentation rate

NSAIDs Nonsteroidal anti-inflammatory drugs

TSH Thyroid-stimulating hormone

FT3 Free triiodothyronine;

FT4 Free thyroxine

ATA American Thyroid Association

LD low-dose

RD regular dose

PDN prednisone

Funding statements: This work was supported by The Introduction of talents Foundation of Yijishan hospital (Grant No.YR201612)；Natural Science Foundation of Anhui Province（Grant No. 2108085MH267）；Key research and development projects in Anhui Province（Grant No.202104j07020023）; Funding of "Climbing Peak" Training Program for Innovative Technology team of Yijishan Hospital, Wannan Medical College（Grant No.PF2019013）；Funding of "Peak" Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College（Grant No.GF2019J07）; The academic and technological leader Foundation of Anhui Province in China（Grant No.2017H120）；Funding of Anhui Provincial Department of Education（Grant No.SK2019ZD18）.

Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Ethical approval: The protocol was approved by the Institutional Review Board of the First Affiliated Hospital (Yijishan hospital) of Wannan Medical College and was implemented in accordance with provisions of the Declaration of Helsinki. Each patient provided written informed consent before beginning the study procedure.

Consent to participate: Informed consent was obtained from all individual participants included in the study.

Consent to publish: The authors agree to publication in the Endocrine.

Acknowledgements: The work was supported by The Introduction of talents Foundation of Yijishan hospital (Grant No.YR201612)；Natural Science Foundation of Anhui Province（Grant No. 2108085MH267）；Key research and development projects in Anhui Province（Grant No.202104j07020023）; Funding of "Climbing Peak" Training Program for Innovative Technology team of Yijishan Hospital, Wannan Medical College（Grant No.PF2019013）； Funding of "Peak" Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College（Grant No.GF2019J07）; The academic and technological leader Foundation of Anhui Province in China（Grant No.2017H120）；Funding of Anhui Provincial Department of Education（Grant No.SK2019ZD18）.

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Efficacy of two different dosages of prednisolone for treatment of subacute thyroiditis: a single-center, prospective, randomized, open-label, non-inferiority trial

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